By: Cindy Van, PharmD Candidate c/o 2022, Shireen Farzadeh, PharmD, BCPS

             Insomnia is a condition characterized by difficulty falling asleep, staying asleep, or both, despite an adequate opportunity to sleep. Consequently, insomnia can lead to daytime fatigue, difficulty concentrating, and irritability. This condition can be categorized into short-term and chronic insomnia. While short-term insomnia lasts for less than 3 months, chronic insomnia lasts for more than 3 months and occurs at least 3 times per week. Short-term insomnia is more common than chronic insomnia, prevalent in 30-50% versus 5-10% of the population, respectively.¹ The orexin neuropeptide signaling system plays a role in wakefulness and may contribute to insomnia. Orexin receptor antagonists are a class of medications used to treat insomnia. One example is suvorexant (Belsomra ®) which blocks the binding of orexin A and B to receptors OX1R and OX2R, with a greater inhibition of OX2R to promote sleep. In December 2019, another orexin receptor antagonist, lemborexant (Dayvigo ®), was approved based on the SUNRISE 1 and 2 trials. ^2-4

SUNRISE 1 was a randomized, double-blind, placebo- and active-controlled, multi-center, parallel-group phase 3 study, in which results were evaluated after 1 month. The study included adult female patients aged 55 years and older and male patients, aged 65 years and older, who met the DSM-5 criteria for insomnia disorder. The trial included a two-week placebo run-in period during the pre-randomization phase, which lasted up to 35 days, and a two-week period without treatment prior to the end of the study visit. Out of 1006 patients randomized, patients received the following agents immediately before bedtime: placebo (n=208), lemborexant 5 mg (n=266), lemborexant 10 mg (n=269), or zolpidem ER 6.25 mg (n=263). The study met statistical significance for the primary endpoint of change from baseline in sleep latency (time to fall asleep) to persistent sleep for lemborexant therapy vs placebo. The primary end point was measured using polysomnography after 1 month. Patients who received lemborexant 5 mg and 10 mg had a reduced sleep latency of 23% (P <0.001) and 28% (P <0.001), respectively. The study also met statistical significance for the secondary endpoints of changes from baseline in sleep efficiency and wake-after-sleep onset vs placebo, as well as the wake-after-sleep onset during the second half of the night vs zolpidem. Patients who received lemborexant 5 mg and 10 mg had an increased sleep efficiency from baseline of 7% (P <0.001) and 8% (P <0.001), wake- after-sleep onset reduction of 24 minutes (P <0.001) and 25 minutes (P <0.001), and wake- after-sleep onset in the second half of the night reduction by 7 min (P = 0.004) and 8 min (P <0.001). Although the following severe adverse events occurred, all were determined by the investigator to be unrelated to the treatment: falls (lemborexant 5 mg: n = 4), sleep paralysis (lemborexant 5 mg: n = 10, lemborexant 10 mg: n = 3). The most common mild adverse events were headache and somnolence in both the treatment and placebo groups, but differences were not statistically significant. Limitations of the SUNRISE 1 trial included recall bias and the limited inclusion criteria of women aged 55 years and older and men aged 65 and older with sleep maintenance insomnia, yet all patients in the zolpidem group received 6.25 mg nightly, the recommended maximum dose for patients aged 65 and older. Overall, the study’s results demonstrated that lemborexant was well tolerated and effective, therefore leading to the SUNRISE 2 trial. ^5,6

SUNRISE 2 was a randomized, double-blind, placebo-controlled, multicenter trial in adult patients ranging from 18 to 84 years of age who met DSM-5 criteria for insomnia disorder. The length of the study was 12 months, consisting of a 6-month placebo-controlled period followed by a 6-month active-treatment only period. Patients ≥18 years old with insomnia were included in the trial and randomized. A total of 949 adult patients were randomized into the following groups: placebo (n=325), lemborexant 5mg (n=323), and lemborexant 10mg (n=323) which were to be taken once nightly. The study met statistical significance for the primary efficacy endpoint in mean change from baseline to end of treatment (6 months) for patient-reported subjective sleep onset latency (sSOL), with a reduction by 22 minutes, 28 minutes, and 11 minutes in the lemborexant 5 mg, lemborexant 10 mg, and placebo group, respectively (P < 0.0001). The study also met statistical significance in the secondary endpoint, subjective wake-after-sleep onset (sWASO), with a reduction by 82 minutes, 86 minutes, and 103 minutes in the lemborexant 5 mg, lemborexant 10 mg, and placebo group, respectively (P < 0.001). In addition, a significantly greater proportion of sleep onset responders was observed at the end of month 6 with lemborexant 5mg (31%; p < 0.001) and lemborexant 10mg (30%; p < 0.001) compared to placebo (18%). It is worthy to note that the findings are based on patient reports using a sleep diary, and therefore, are subjective in nature and may pose a limitation to the study. Another study limitation was the lack of flexible dosing, in which patients were not able to titrate doses. Similar to the adverse events occurring in the SUNRISE 1 trial, none demonstrated statistical significance and the most common adverse events were somnolence and headaches. Overall, the results of the study demonstrated long-term efficacy and tolerability and led to the FDA-approval of lemborexant. ⁷

Insomnia is one of the most common sleep-wake disorders with high prevalence. Not only does this condition cause social losses such as long absences, but it can also reduce productivity for students and workers alike. In this clinical study, lemborexant appears to be the first FDA- approved medication to report safety data over a 12-month period along with sleep onset and sleep maintenance efficacy data over a six-month period. ² As such, it is a viable solution for patients experiencing insomnia. In the community setting, pharmacists play an important role in counseling patients to consider starting non-pharmacological therapy prior to pharmacological agents. Non-pharmacological therapy includes, sleep hygiene education, and behavioral modifications such as avoiding caffeine before bed and not going to bed unless sleepy. In the case of lemborexant, due to an increased likelihood of somnolence as compared with placebo, patients are advised to get adequate sleep and to avoid operating machinery, as it can affect cognitive performance. With appropriate non-pharmacological and potentially, pharmacological management, patients can expect to see improvements to their insomnia.

Sources:

1. Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2017;13(2):307-349.
2. U.S. FDA Approves Eisai’s Dayvigo TM (Lemborexant) for Treatment of Insomnia in Adult Patients. Eisai Web Site. https://www.eisai.com/news/2019/news201993.html. Published December 23, 2019. Accessed June 13, 2020.
3. Suvorexant (oral). In: Lexi-Drugs. Hudson, OH: Lexi-Comp, Inc. Updated June 9, 2020; Accessed June 13, 2020.
4. Lemborexant (oral). In: Lexi-Drugs. Hudson, OH: Lexi-Comp, Inc Updated June 1, 2020; Accessed June 12, 2020.
5. Zolpidem (oral). In: Lexi-Drugs. Hudson, OH: Lexi-Comp, Inc. Updated June 9, 2020; Accessed June 13, 2020.
6. Rosenberg R, Murphy P, Zammit G, et al. Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia Disorder: A Phase 3 Randomized Clinical Trial. JAMA Netw Open. 2019;2(12):e1918254.
7. Kärppä M, Yardley J, Pinner K, et al. Long-term efficacy and tolerability of lemborexant compared with placebo in adults with insomnia disorder: results from the phase 3 randomized clinical trial SUNRISE 2. Sleep. 2020;43(9).

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