Clinical Trials

Date: 2017-06-06

Type of information: Results

phase: 3

Announcement: presentation of results at the 31st Associated Professional Sleep Societies (APSS) Annual SLEEP Meeting

Company: Jazz Pharmaceuticals (Ireland)

Product: solriamfetol - JZP-110 (formerly known as ADX-N05)

Action mechanism:

dopamine and norepinephrine reuptake inhibitor (DNRI). JZP-110 is a selective dopamine and norepinephrine reuptake inhibitor (DNRI) in development for treatment of excessive sleepiness in adult patients with narcolepsy, OSA, and Parkinson's disease. In 2014, Jazz Pharmaceuticals acquired a license to develop and commercialize JZP-110 from SK Biopharmaceuticals, which discovered the compound.
Jazz Pharmaceuticals has worldwide development, manufacturing, and commercialization rights to JZP-110, excluding certain jurisdictions in Asia . SK Biopharmaceuticals maintains rights in Korea , Japan , China , Taiwan , Singapore , Indonesia , India , Philippines ,Thailand , Malaysia , Vietnam , and Hong Kong . JZP-110 has orphan drug designation in the United States for narcolepsy.
Across the entire JZP-110 development program, over 2,000 subjects have enrolled in 20 studies. The JZP-110 Phase 3 clinical program includes one study evaluating excessive sleepiness in adult patients with narcolepsy (TONES 2), two studies evaluating excessive sleepiness in adult patients with OSA (TONES 3 and TONES 4), and an open-label, long-term safety and maintenance of efficacy study (TONES 5) in the treatment of excessive sleepiness in patients with narcolepsy or OSA. Enrollment is complete in all studies that are expected to support Jazz Pharmaceuticals' planned JZP-110 New Drug Application (NDA) submission to the FDA in late 2017.

Disease: excessive sleepiness

Therapeutic area: Rare diseases

Country: Canada, Finland, France, Germany, Sweden, USA

Trial details:

The Treatment of OSA and Narcolepsy Excessive Sleepiness (TONES) Phase 3 program is comprised of four studies, one study evaluating excessive sleepiness in adult patients with narcolepsy (TONES 2), two studies evaluating excessive sleepiness in adult patients with OSA (TONES 3 and TONES 4), and an open-label, long-term safety and maintenance of efficacy study (TONES 5) in the treatment of excessive sleepiness in patients with narcolepsy or OSA.
Clinical Program Study Design: Approximately 880 patients in the aggregate are expected to be enrolled in the three Phase 3 studies to be conducted across 67 medical centers in the U.S., Canada and EU. The co-primary endpoints for all three Phase 3 clinical studies -- the Maintenance of Wakefulness Test (MWT) and the Epworth Sleepiness Scale (ESS) -- will measure patients' improvement in ability to stay awake and in sleepiness. Up to 450 patients are expected to be enrolled in the open-label, long-term safety extension study.
Study 14-002: A 12-week, double-blind, randomized, placebo-controlled, multi-center, four-treatment parallel group study of the safety and efficacy of JZP-110 in the treatment of EDS in adult patients with narcolepsy.
Study 14-003: A 12-week double-blind, placebo-controlled, randomized, multi-center study of the safety and efficacy of JZP-110 in the treatment of EDS in adult patients with OSA.
Study 14-004: A six-week, double-blind, placebo-controlled, randomized-withdrawal, multi-center study of the safety and efficacy of JZP-110 in the treatment of EDS in adult patients with OSA.
Study 14-005: A long-term (52 week) open-label safety and maintenance of efficacy study of JZP-110 in the treatment of EDS in adult patients with narcolepsy or with OSA to assess the long-term safety and maintenance of efficacy in patients.
(NCT02348606, NCT02348593, NCT02348619)

Latest news:

• On June 6, 2017, Jazz Pharmaceuticals presented positive efficacy results from its global multicenter studies (TONES 3 and TONES 4) of JZP-110 in adult patients with excessive sleepiness associated with obstructive sleep apnea (OSA). The data were presented in a poster session at the 31st Associated Professional Sleep Societies (APSS) Annual SLEEP Meeting in Boston.
TONES 3 was a 12-week, 5-arm, parallel-group, double-blind, placebo-controlled, randomized Phase 3 study that evaluated the safety and efficacy of JZP-110 at 300 mg, 150 mg, 75 mg, and 37.5 mg compared to placebo, in adults with excessive sleepiness in OSA. Patients (N=476) were randomized 1:1:2:2:2 to JZP-110 37.5 mg (n=59), 75 mg (n=61), 150 mg (n=118), 300 mg (n=119), or placebo (n=119). The co-primary endpoints were the change in mean sleep latency on the Maintenance of Wakefulness Test (MWT) and in the Epworth Sleepiness Scale (ESS) score, from baseline to week 12. The key secondary endpoint was the percentage of patients who reported improvement on the Patient Global Impression of Change (PGIc) scale, a patient-reported measure of overall condition from baseline to week 12.
In adult patients with OSA, JZP-110 at all doses demonstrated statistically significant improvements on the co-primary endpoints of mean sleep latency on the MWT and the ESS from baseline to week 12 compared to placebo. The endpoints of MWT and ESS measure patients' ability to stay awake and patients' subjective levels of sleepiness, respectively. JZP-110 increased the mean MWT sleep latency by more than 10 minutes at all time points at the 150 and 300 mg doses. JZP-110 decreased mean ESS scores by more than 7 points at the 150 and 300 mg doses at week 12.
On the key secondary endpoint of the PGIc scale, patients reported significant overall improvement compared to placebo at week 12 on all doses of JZP-110 except for 37.5 mg. Approximately 90% of patients reported overall improvement on the 150 and 300 mg doses at week 12. Results from the primary analysis of the co-primary endpoints of MWT and ESS, and analysis of the key secondary endpoint of PGIc were:

TONES 3 Study Results (mITT population, N=459)	Change (SE) from Baseline to Week 12
TONES 3 Study Results (mITT population, N=459)	JZP-110 300 mg (N=115)	JZP-110 150 mg (N=116)	JZP-110 75 mg (N=58)	JZP-110 37.5 mg (N=56)	Placebo (N=114)
Mean Sleep Latency on Maintenance of Wakefulness Test (MWT): Increased ability to stay awake	13.0 min (1.0) p<0.0001	11.0 min (1.0) p<0.0001	9.1 min (1.4) p<0.0001	4.7 min (1.4) p<0.05	0.2 min (1.0)
Epworth Sleepiness Scale (ESS): Decreased subjective sleepiness	-7.9 (0.5) p<0.0001	-7.7 (0.4) p<0.0001	-5.0 (0.6) p<0.05	-5.1 (0.6) p<0.05	-3.3 (0.5)
Patient Global Impression-Change (PGIc): Minimal, much, or very much improvement	88.7% p<0.0001	89.7% p<0.0001	72.4% p<0.05	55.4% p=0.4447	49.1%

Of the 476 randomized subjects, 404 completed the 12-week treatment. Twenty-nine patients (6.1%) in the safety population: four patients (3.4%) on placebo and 25 (7.0%) on JZP-110, discontinued due to treatment emergent adverse events (TEAEs). The most commonly reported TEAEs (occurring in >5% of patients across all doses of JZP-110) in the TONES 3 study were headache, nausea, decreased appetite, anxiety, and nasopharyngitis. There were seven serious TEAEs reported in five patients: goiter (n=1), and a motor vehicle accident, back pain, and sciatica (n=1) in two patients on placebo; bile duct obstruction (n=1) and streptococcal endocarditis (n=1) in two patients on JZP-110 37.5 mg; and hyperglycemia (n=1) in one patient on JZP-110 150 mg. One subject had a non-treatment emergent SAE of coronary artery disease that started prior to receiving JZP-110 300 mg and that was not reported until after dosing. TEAEs and discontinuations due to an AE were most common at the JZP-110 300 mg dose.

TONES 4 was a six-week Phase 3 study comprising a two-week flexible-dose titration phase followed by two-weeks of stable dose treatment. Patients who reported 'much' or 'very much' improvement and who had numerical improvements on the MWT and ESS at the end of the stable dose phase (week 4) then entered a two-week, placebo-controlled, double-blind randomized withdrawal phase. In this study, 174 patients were titrated to a maximum tolerated dose over a two-week period, and 157 patients continued on that dose for two weeks in the stable dose phase. The primary analysis (n=122 in the modified intent to treat (mITT) population) evaluated the difference between JZP-110 treatment versus placebo on the co-primary endpoints of MWT and ESS, measured from the end of the stable dose phase at week 4 to the end of the randomized withdrawal phase at week 6.

Patients who completed the 4-week treatment and remained on JZP-110 did not demonstrate loss of efficacy relative to those who were randomized to placebo.

Results from the primary analysis of the co-primary endpoints of MWT and ESS, and analysis of the key secondary endpoint of PGIc were:

TONES 4 Study Results (mITT population)	Change (SE) from Week 4 to Week 6
TONES 4 Study Results (mITT population)	JZP-110 (N=60)	Placebo (N=62)
Mean Sleep Latency on Maintenance of Wakefulness Test (MWT): Ability to stay awake	-1.0 min (1.4) p<0.0001	-12.1 min (1.3)
Epworth Sleepiness Scale (ESS): Subjective sleepiness	-0.1 (0.7) p<0.0001	4.5 (0.7)
Patient Global Impression-Change (PGIc): Minimally, much, or very much worse	20.0% p<0.0001	50.0%

During the double-blind withdrawal phase (weeks 4 to 6), patients who continued on JZP-110 remained improved on the MWT and ESS. Patients who switched to placebo showed worsening of sleepiness, with mean MWT sleep latency decreased by 12.1 minutes from week 4 to week 6 (compared with a decrease of 1.0 minute for those who remained on JZP-110, p<0.0001) and mean ESS scores increased by 4.5 minutes (compared to a mean decrease of 0.1 minutes for those who stayed on JZP-110, p<0.0001).

A significantly higher percentage of patients who were switched to placebo experienced a worsening of their overall condition on the PGIc as compared with patients who stayed on JZP-110 (p<0.0001).
There were no serious TEAEs. Six patients (3.4%) withdrew from the study due to TEAEs. Most TEAEs occurred during the titration phase of the study. The most common TEAEs (occurring in =5% patients) during the titration phase were headache, dry mouth, nausea, dizziness, and insomnia.
• On November 28, 2016, Jazz Pharmaceuticals announced that patient enrollment has been completed in its Phase 3 study evaluating JZP-110 in excessive sleepiness (ES) associated with narcolepsy. The Phase 3 narcolepsy study was a double-blind, placebo-controlled, multiple-center study evaluating the safety and efficacy of JZP-110 in the treatment of ES in adult patients with narcolepsy. The study enrolled 240 patients. The co-primary endpoints were the Maintenance of Wakefulness Test and the Epworth Sleepiness Scale. These are validated endpoints, commonly used in clinical trials, that measure the ability to stay awake and the severity of excessive sleepiness, respectively, in patients
• On September 26, 2016, Jazz Pharmaceuticals announced that patient enrollment has been completed for its two Phase 3 studies evaluating JZP-110 in excessive sleepiness (ES) associated with obstructive sleep apnea (OSA). The two Phase 3 OSA studies enrolled approximately 654 patients. Both studies were double-blind, placebo-controlled, multiple-center studies evaluating the safety and efficacy of JZP-110 in the treatment of ES in adult patients with OSA. Study 14-003 evaluated four doses of JZP-110 or placebo for a 12-week period and study 14-004 was a six-week, flexible-dose, randomized withdrawal study. The studies have co-primary endpoints of the Epworth Sleepiness Scale (ESS) and the Maintenance of Wakefulness Test (MWT). These are validated endpoints, used in clinical practice, to measure the severity of excessive sleepiness and ability to stay awake in patients.
• On June 14, 2016, Jazz Pharmaceuticals announced results from a Human Abuse Liability (HAL) study of JZP-110, an investigational wake-promoting agent in Phase 3 development for the treatment of excessive sleepiness (ES) in adult patients with narcolepsy or with obstructive sleep apnea (OSA). The data will be presented at the 30th Associated Professional Sleep Societies (APSS) Annual SLEEP Meeting, taking place June 11-15, 2016 in Denver, Colorado . The HAL study was a randomized, double-blind, placebo-controlled, six-sequence crossover study evaluating the abuse potential of JZP-110 relative to the Schedule IV stimulant phentermine in 43 adults with a recent history of recreational polydrug use, including stimulants, who met study entry criteria. Subjects were randomized to one of six test sequences, in which they received a single treatment with one of the six study drugs (JZP-110 at 300 mg, 600 mg, and 1200 mg; phentermine at 45 mg and 90 mg; and placebo), with a two-day washout period between each treatment. The study evaluated effects that are predictive of abuse potential. The primary endpoint was Liking at the Moment across the first 12 hours after drug administration based on a subject-reported 100-point bipolar liking/disliking visual analog scale (VAS), a standard measure of abuse potential in HAL studies. Key secondary endpoints were retrospective VAS ratings at 24 hours after drug administration for Overall Next Day Drug Liking and how much the participant would like to Take the Drug Again. Results: On the primary endpoint, all doses of JZP-110 had significantly lower ratings of peak (Emax) Liking at the Moment compared to 90 mg of phentermine (P<0.05) and had significantly greater ratings of peak Liking at the Moment compared to placebo (P<0.001). On the secondary endpoint of Overall Next Day Drug Liking, JZP-110 at 600 mg and at 1200 mg had significantly lower measures compared to both doses of phentermine (P<0.05). JZP-110 at 300 mg was not statistically different from 45 mg of phentermine (p=0.070). JZP-110 at 600 mg and at 1200 mg did not have any statistical difference in Overall Next Day Drug Liking measures compared to placebo. JZP-110 at 300 mg had higher measures of Overall Next Day Drug Liking at 24 hours compared to placebo (p=0.021). On the secondary endpoint of willingness to Take the Drug Again, JZP-110 at all doses had significantly lower measures compared to both doses of phentermine (P<0.05). All doses of JZP-110 had higher ratings of willingness to Take the Drug Again relative to placebo (P<0.05). Of the 43 adult subjects, 37 completed all six test treatment phases. Two subjects discontinued for treatment emergent adverse events (TEAEs) after receiving 1200 mg of JZP-110. TEAEs were dose-dependent for JZP-110 and phentermine and none were serious or severe. The most frequent TEAEs at the 1200 mg dose of JZP-110 were: hypervigilance, elevated mood, dry mouth, nausea, feelings of relaxation, decreased appetite, hyperhidrosis, insomnia, headache, restlessness, and palpitations.
• On June 8, 2015, Jazz Pharmaceuticals announced that the first patients have been enrolled in a Phase 3 clinical development program evaluating the safety and efficacy of JZP-110, as a wake-promoting agent in the treatment of excessive daytime sleepiness ( EDS ) in adult patients with narcolepsy or with obstructive sleep apnea (OSA). The JZP-110 clinical development program includes three Phase 3 studies being conducted in the United States, Canada and the European Union (EU). The program also includes an open-label extension study to evaluate the long-term safety of JZP-110.
• On June 2, 2014, Jazz Pharmaceuticals presented data from the Phase 2b study evaluating JZP-110 (formerly known as ADX-N05) as a potential new treatment for the symptoms of excessive daytime sleepiness ( EDS ) in adults with narcolepsy. In the study presented at a late-breaker session during SLEEP 2014, the 28th Annual Meeting of the Associated Professional Sleep Societies (APSS), in Minneapolis, Minn, all primary and secondary endpoints were met and patients treated with JZP-110 experienced statistically significant improvements in objective and subjective symptoms of EDS. Based on these data, Jazz Pharmaceuticals plans to evaluate JZP-110 in Phase 3 clinical studies in patients with EDS associated with narcolepsy and in patients with EDS associated with obstructive sleep apnea (OSA), pending discussions with regulatory agencies. Patients treated with JZP-110 experienced statistically significant results in both primary endpoints and the secondary endpoint (ESS) at weeks four and 12 compared to those receiving placebo. Patients who received treatment experienced the following results:

Phase 2b Study Results Treated Population = subjects with = 1 post-randomization assessment	Week 4		Week 12
	JZP-110(150 mg)	Placebo	JZP-110 (150 mg through week 4 followed by 300 mg for 8 weeks)	Placebo
Sleep Onset Latency (SOL) on the Maintenance of Wakefulness Test (MWT):Increase in time to fall asleep	9.5 min N=40	1.4 min N=45	12.8 min N=40	2.1 min N=45
	p<0.0001		p<0.0001
Clinical Global Impression-Change (CGIC): Symptoms "much improved" or "very much improved"	80% N=43	51% N=47	86% N=43	38% N=47
	p<0.0066		p<0.0001
Epworth Sleepiness Scale (ESS): Decrease in overall sleepiness	-5.6 points N=43	-2.4 points N=47	-8.5 points N=43	-2.5 points N=47
	p=0.0038		p<0.0001

In this study, JZP-110 was generally well-tolerated. Most adverse events (AEs) were mild to moderate in severity. The most common AEs (>=10%) more frequently observed with JZP-110 than with placebo were headache, nausea, diarrhea, insomnia, decreased appetite and anxiety. Two subjects in the JZP-110 group reported serious AEs (conversion disorder and acute cholecystitis) that were attributed by the investigators as unlikely to be related to the compound. Three subjects (6.8%) in the JZP-110 group and two subjects (4%) in the placebo group discontinued due to adverse events (AEs). The three subjects in the JZP-110 group discontinued for the following reasons: one subject with conversion disorder; one subject with bruxism, insomnia and anxiety; and the third subject with palpitations and initial insomnia.
This Phase 2b, double-blind, placebo-controlled, parallel-group, multicenter study evaluated the safety and efficacy of JZP-110 over 12 weeks in 93 subjects aged 18-70 years with an ICSD-2 diagnosis of narcolepsy. The study was sponsored by Aerial BioPharma, LLC , from which Jazz Pharmaceuticals acquired the rights to JZP-110 in early 2014. Subjects were randomized to once-daily placebo (n=49) or JZP-110 (n=44). JZP-110 was administered at a dose of 150 mg/day during weeks one through four and at a dose of 300 mg/day during weeks five through 12. Co-primary efficacy endpoints measuring JZP-110's effect on EDS were change from baseline to last assessment in the length of time it took to fall asleep as measured by the average sleep onset latency (SOL) on the Maintenance of Wakefulness Test (MWT), an objective measure of the severity of EDS , and symptom improvement as measured by the Clinical Global Impression-Change (CGIC), a subjective physician-completed scale. The change from baseline at weeks four and 12 on the Epworth Sleepiness Scale (ESS), a subjective patient-completed measure of sleepiness, was a secondary endpoint.

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