Lemborexant

NUTLEY, N.J., April 12, 2024 /PRNewswire/ -- Eisai Inc. announced today the Company will present findings from its robust neurology portfolio, including data from the Phase 3 Clarity AD trial for LEQEMBI® (lecanemab-irmb), Eisai's anti-amyloid beta (Aβ) protofibril* antibody for the treatment of early Alzheimer's disease (AD), as well as data on its insomnia dual orexin receptor antagonist DAYVIGO® (lemborexant) CIV at the American Academy of Neurology® (AAN) Annual Meeting. The meeting will be held in Denver, Colorado, and virtually from April 13-18, 2024. "Eisai is proud to share the latest data from our neurology portfolio, including efficacy results on continued treatment with our therapy for early AD," said Michael Irizarry, M.D., MPH, Deputy Chief Clinical Officer and Senior Vice President of Clinical Research at Eisai Inc. "AD is a progressive, debilitating, and fatal neurodegenerative condition, and the earlier mild cognitive impairment (MCI) due to AD and mild AD dementia are diagnosed and treated, the greater the opportunity for the patient to benefit." In addition to the data being presented, Eisai will host an educational industry therapeutic update featuring a discussion with clinical experts Julie Schwartzbard, M.D., FAAN, Marwan N. Sabbagh, M.D., FAAN, FANA, and Justin B. Moon, M.D., MPH, on AD pathophysiology, the importance of early AD diagnosis and treatment initiation, and the application of emerging AD treatments. Eisai will also host an industry therapeutic update with David C. Weisman, M.D., who will review pivotal Phase 3 data from the Clarity AD study and clinical considerations for the use of LEQEMBI in early AD, including real-world experience. *Protofibrils are believed to contribute to the brain injury that occurs with AD and are considered to be the most toxic form of Aβ, having a primary role in the cognitive decline associated with this progressive, debilitating condition.1,2 Protofibrils cause injury to neurons in the brain, which in turn, can negatively impact cognitive function via multiple mechanisms, not only increasing the development of insoluble Aβ plaques, but also increasing direct damage to brain cell membranes and the connections that transmit signals between nerve cells or nerve cells and other cells. It is believed the reduction of protofibrils may prevent the progression of AD by reducing damage to neurons in the brain and cognitive dysfunction.3 INDICATION AND IMPORTANT SAFETY INFORMATION INDICATION LEQEMBI is indicated for the treatment of Alzheimer's disease. Treatment with LEQEMBI should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. IMPORTANT SAFETY INFORMATION CONTRAINDICATION LEQEMBI is contraindicated in patients with serious hypersensitivity to lecanemab-irmb or to any of the excipients of LEQEMBI. Reactions have included angioedema and anaphylaxis. WARNINGS AND PRECAUTIONS AMYLOID RELATED IMAGING ABNORMALITIES LEQEMBI can cause ARIA-E and ARIA-H. ARIA-E can be observed on MRI as brain edema or sulcal effusions, and ARIA-H as microhemorrhage and superficial siderosis. ARIA can occur spontaneously in patients with Alzheimer's disease. ARIA-H associated with monoclonal antibodies directed against aggregated forms of beta amyloid generally occurs in association with an occurrence of ARIA-E. ARIA-H and ARIA-E can occur together. ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, rarely can occur. Reported symptoms associated with ARIA may include headache, confusion, visual changes, dizziness, nausea, and gait difficulty. Focal neurologic deficits may also occur. Symptoms associated with ARIA usually resolve over time. ARIA Monitoring and Dose Management Guidelines Obtain recent baseline brain magnetic resonance imaging (MRI) prior to initiating treatment with LEQEMBI. Obtain an MRI prior to the 5th, 7th and 14th infusions. Recommendations for dosing in patients with ARIA-E and ARIA-H depend on clinical symptoms and radiographic severity. Depending on ARIA severity, use clinical judgment in considering whether to continue dosing, temporarily discontinue treatment, or permanently discontinue LEQEMBI. Enhanced clinical vigilance for ARIA is recommended during the first 14 weeks of treatment with LEQEMBI. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including MRI if indicated. If ARIA is observed on MRI, careful clinical evaluation should be performed prior to continuing treatment. There is no experience in patients who continued dosing through symptomatic ARIA-E or through asymptomatic, but radiographically severe, ARIA-E. There is limited experience in patients who continued dosing through asymptomatic but radiographically mild to moderate ARIA-E. There are limited data in dosing patients who experienced recurrent ARIA-E. Incidence of ARIA In Study 2, symptomatic ARIA occurred in 3% (29/898) of LEQEMBI-treated patients. Serious symptoms associated with ARIA were reported in 0.7% (6/898) of patients treated with LEQEMBI. Clinical symptoms associated with ARIA resolved in 79% (23/29) of patients during the period of observation. Including asymptomatic radiographic events, ARIA was observed in LEQEMBI: 21% (191/898); placebo: 9% (84/897). ARIA-E was observed in LEQEMBI: 13% (113/898); placebo: 2% (15/897). ARIA-H was observed in LEQEMBI: 17% (152/898); placebo: 9% (80/897). There was no increase in isolated ARIA-H for LEQEMBI vs placebo. ApoE ε4 Carrier Status and Risk of ARIA In Study 2, 16% (141/898) of patients in the LEQEMBI arm were ApoE ε4 homozygotes, 53% (479/898) were heterozygotes, and 31% (278/898) were noncarriers. The incidence of ARIA was higher in ApoE ε4 homozygotes (LEQEMBI: 45%; placebo: 22%) than in heterozygotes (LEQEMBI: 19%; placebo: 9%) and noncarriers (LEQEMBI: 13%; placebo: 4%). Among patients treated with LEQEMBI, symptomatic ARIA-E occurred in 9% of ApoE ε4 homozygotes compared with 2% of heterozygotes and 1% of noncarriers. Serious events of ARIA occurred in 3% of ApoE ε4 homozygotes, and approximately 1% of heterozygotes and noncarriers. The recommendations on management of ARIA do not differ between ApoE ε4 carriers and noncarriers. Radiographic Findings The majority of ARIA-E radiographic events occurred early in treatment (within the first 7 doses), although ARIA can occur at any time and patients can have more than 1 episode. The maximum radiographic severity of ARIA-E in patients treated with LEQEMBI was mild in 4% (37/898), moderate in 7% (66/898), and severe in 1% (9/898). Resolution on MRI occurred in 52% of ARIA-E patients by 12 weeks, 81% by 17 weeks, and 100% overall after detection. The maximum radiographic severity of ARIA-H microhemorrhage in LEQEMBI-treated patients was mild in 9% (79/898), moderate in 2% (19/898), and severe in 3% (28/898) of patients; superficial siderosis was mild in 4% (38/898), moderate in 1% (8/898), and severe in 0.4% (4/898). Among LEQEMBI-treated patients, the rate of severe radiographic ARIA-E was highest in ApoE ε4 homozygotes 5% (7/141), compared to heterozygotes 0.4% (2/479) or noncarriers 0% (0/278). Among LEQEMBI-treated patients, the rate of severe radiographic ARIA-H was highest in ApoE ε4 homozygotes 13.5% (19/141), compared to heterozygotes 2.1% (10/479) or noncarriers 1.1% (3/278). Intracerebral Hemorrhage Intracerebral hemorrhage >1 cm in diameter was reported in 0.7% (6/898) of patients in Study 2 after treatment with LEQEMBI compared to 0.1% (1/897) on placebo. Fatal events of intracerebral hemorrhage in patients taking LEQEMBI have been reported. Concomitant Antithrombotic Medication: In Study 2, baseline use of antithrombotic medication (aspirin, other antiplatelets, or anticoagulants) was allowed if the patient was on a stable dose. The majority of exposures to antithrombotic medications were to aspirin. Antithrombotic medications did not increase the risk of ARIA with LEQEMBI. The incidence of intracerebral hemorrhage was 0.9% (3/328 patients) in patients taking LEQEMBI with a concomitant antithrombotic medication at the time of the event compared to 0.6% (3/545 patients) in those who did not receive an antithrombotic. Patients taking LEQEMBI with an anticoagulant alone or combined with an antiplatelet medication or aspirin had an incidence of intracerebral hemorrhage of 2.5% (2/79 patients) compared to none in patients who received placebo. Because intracerebral hemorrhages >1 cm in diameter have been observed in patients taking LEQEMBI, additional caution should be exercised when considering the administration of anticoagulants or a thrombolytic agent (e.g., tissue plasminogen activator) to a patient already being treated with LEQEMBI. Other Risk Factors for Intracerebral Hemorrhage: Patients were excluded from enrollment in Study 2 for findings on neuroimaging that indicated an increased risk for intracerebral hemorrhage. These included findings suggestive of cerebral amyloid angiopathy (prior cerebral hemorrhage >1 cm in greatest diameter, >4 microhemorrhages, superficial siderosis, vasogenic edema) or other lesions (aneurysm, vascular malformation) that could potentially increase the risk of intracerebral hemorrhage. The presence of an ApoE ε4 allele is also associated with cerebral amyloid angiopathy, which has an increased risk for intracerebral hemorrhage. Caution should be exercised when considering the use of LEQEMBI in patients with factors that indicate an increased risk for intracerebral hemorrhage and in particular for patients who need to be on anticoagulant therapy. HYPERSENSITIVITY REACTIONS Hypersensitivity reactions, including angioedema, bronchospasm, and anaphylaxis, have occurred in LEQEMBI-treated patients. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity reaction, and initiate appropriate therapy. INFUSION-RELATED REACTIONS In Study 2, infusion-related reactions were observed in LEQEMBI: 26% (237/898); placebo: 7% (66/897), and the majority of cases in LEQEMBI-treated patients (75%, 178/237) occurred with the first infusion. Infusion-related reactions were mostly mild (69%) or moderate (28%) in severity. Infusion-related reactions resulted in discontinuations in 1% (12/898) of LEQEMBI-treated patients. Symptoms of infusion-related reactions included fever and flu-like symptoms (chills, generalized aches, feeling shaky, and joint pain), nausea, vomiting, hypotension, hypertension, and oxygen desaturation. In the event of an infusion-related reaction, the infusion rate may be reduced, or the infusion may be discontinued, and appropriate therapy initiated as clinically indicated. Prophylactic treatment with antihistamines, acetaminophen, nonsteroidal anti-inflammatory drugs, or corticosteroids prior to future infusions may be considered. ADVERSE REACTIONS In Study 2, the most common adverse reaction leading to discontinuation of LEQEMBI was ARIA-H microhemorrhages that led to discontinuation in 2% (15/898) of patients treated with LEQEMBI compared to <1% (1/897) of patients on placebo. In Study 2, the most common adverse reactions reported in ≥5% of patients treated with LEQEMBI (N=898) and ≥2% higher than placebo (N=897) were infusion-related reactions (LEQEMBI: 26%; placebo: 7%), ARIA-H (LEQEMBI: 14%; placebo: 8%), ARIA-E (LEQEMBI: 13%; placebo: 2%), headache (LEQEMBI: 11%; placebo: 8%), superficial siderosis of central nervous system (LEQEMBI: 6%; placebo: 3%), rash (LEQEMBI: 6%; placebo: 4%), and nausea/vomiting (LEQEMBI: 6%; placebo: 4%). Please see full Prescribing Information for LEQEMBI, including Boxed WARNING. INDICATION DAYVIGO (lemborexant) is an orexin receptor antagonist indicated for the treatment of adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS DAYVIGO is contraindicated in patients with narcolepsy. WARNINGS AND PRECAUTIONS Central Nervous System (CNS) Depressant Effects and Daytime Impairment: DAYVIGO can impair daytime wakefulness. CNS depressant effects may persist in some patients up to several days after discontinuing DAYVIGO. Prescribers should advise patients about the potential for next-day somnolence. Driving ability was impaired in some subjects taking DAYVIGO 10 mg. Risk of daytime impairment is increased if DAYVIGO is taken with less than a full night of sleep remaining or at a higher than recommended dose. If taken in these circumstances, patients should not drive or engage in activities requiring mental alertness. Use with other classes of CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression, which can cause daytime impairment. Dosage adjustments of DAYVIGO and concomitant CNS depressants may be necessary when administered together. Use of DAYVIGO with other insomnia drugs is not recommended. Patients should be advised not to consume alcohol in combination with DAYVIGO. Because DAYVIGO can cause drowsiness, patients, particularly the elderly, are at a higher risk of falls. Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-Like Symptoms: Sleep paralysis, an inability to move or speak for up to several minutes during sleep-wake transitions, hypnagogic/hypnopompic hallucinations, including vivid and disturbing perceptions can occur with DAYVIGO. Prescribers should explain these events to patients. Symptoms similar to mild cataplexy can occur with DAYVIGO and can include periods of leg weakness lasting from seconds to a few minutes, can occur either at night or during the day, and may not be associated with identified triggering event (e.g., laughter or surprise). Complex Sleep Behaviors: Complex sleep behaviors, including sleep-walking, sleep-driving, and engaging in other activities while not fully awake (e.g., preparing and eating food, making phone calls, having sex), have been reported to occur with the use of hypnotics such as DAYVIGO. Events can occur in hypnotic-naïve and hypnotic-experienced persons. Patients usually do not remember these events. Complex sleep behaviors may occur following the first or any subsequent use of DAYVIGO, with or without the concomitant use of alcohol and other CNS depressants. Discontinue DAYVIGO immediately if a patient experiences a complex sleep behavior. Patients with Compromised Respiratory Function: DAYVIGO has been studied in mild to severe Obstructive Sleep Apnea (OSA) and moderate to severe Chronic Obstructive Pulmonary Disease (COPD) in short-term clinical trials. The effect of DAYVIGO on respiratory function should be considered for patients with compromised respiratory function. Worsening of Depression/Suicidal Ideation: Incidence of suicidal ideation or suicidal behavior, as assessed by questionnaire, was higher in patients receiving DAYVIGO than placebo (0.3% for DAYVIGO 10 mg, 0.4% for DAYVIGO 5 mg, and 0.2% for placebo). In primarily depressed patients treated with hypnotics, worsening of depression and suicidal thoughts and actions (including completed suicides) have been reported. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional overdose is more common in this group of patients; therefore, the lowest number of tablets that is feasible should be prescribed at any one time. The emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation. Need to Evaluate for Comorbid Diagnoses: Treatment of insomnia should be initiated only after careful evaluation of the patient. Reevaluate for comorbid conditions if insomnia persists or worsens after 7 to 10 days of treatment. Worsening of insomnia or the emergence of new cognitive or behavioral abnormalities may be the result of an unrecognized underlying psychiatric or medical disorder and can emerge during the course of treatment with sleep-promoting drugs such as DAYVIGO. ADVERSE REACTIONS The most common adverse reaction (reported in 5% of patients treated with DAYVIGO and at least twice the rate of placebo) with DAYVIGO was somnolence (10% for DAYVIGO 10 mg, 7% for DAYVIGO 5 mg, 1% for placebo). DRUG INTERACTIONS CYP3A Inhibitors: The maximum recommended dose of DAYVIGO is 5 mg no more than once per night when co-administered with weak CYP3A inhibitors. Avoid concomitant use of DAYVIGO with strong or moderate CYP3A inhibitors. CYP3A Inducers: Avoid concomitant use of DAYVIGO with moderate or strong CYP3A inducers. USE IN SPECIFIC POPULATIONS Pregnancy and Lactation: There is a pregnancy exposure registry that monitors pregnancy outcomes in women who are exposed to DAYVIGO during pregnancy. Healthcare providers are encouraged to register patients in the DAYVIGO pregnancy registry by calling 1-888-274-2378. There are no available data on DAYVIGO use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Data supports that transfer of lemborexant into breastmilk is low. There are no data on the effects of lemborexant on the breastfed infant, or the effects on milk production. Infants exposed to DAYVIGO through breastmilk should be monitored for excess sedation. Geriatric Use: Exercise caution when using doses higher than 5 mg in patients ≥65 years old. Renal Impairment: Patients with severe renal impairment may experience an increased risk of somnolence. Hepatic Impairment: The maximum recommended dose of DAYVIGO is 5 mg inpatients with moderate hepatic impairment. DAYVIGO is not recommended in patients with severe hepatic impairment. Patients with mild hepatic impairment may experience an increased risk of somnolence. DRUG ABUSE AND DEPENDENCE DAYVIGO is a Schedule IV-controlled substance. Because individuals with a history of abuse or addiction to alcohol or other drugs may be at increased risk for abuse and addiction to DAYVIGO, follow such patients carefully. For more information about DAYVIGO, see full Prescribing Information. [Notes to editors] 1. About Lecanemab (LEQEMBI®) Lecanemab is the result of a strategic research alliance between Eisai and BioArctic. It is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble (protofibril) and insoluble forms of amyloid-beta (Aβ).1,4 Lecanemab is approved in the U.S.,5 Japan,6 and China7. In the U.S., Japan and China, the indications are as follows. U.S.: For the treatment of Alzheimer's disease (AD). It should be initiated in patients with MCI or mild dementia stage of disease.5 Japan: For slowing progression of MCI and mild dementia due to AD.6 China: For the treatment of MCI due to AD and mild AD dementia.7 LEQEMBI's FDA approval was based on Phase 3 data from Eisai's global Clarity AD clinical trial, in which it met its primary endpoint and all key secondary endpoints with statistically significant results.4 The primary endpoint was the global cognitive and functional scale, Clinical Dementia Rating Sum of Boxes (CDR-SB). In the Clarity AD clinical trial, treatment with lecanemab reduced clinical decline on CDR-SB by 27% at 18 months compared to placebo.4 The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, −0.45; 95% confidence interval [CI], −0.67 to −0.23; P<0.001).4 In addition, the secondary endpoint from the AD Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL), which measures information provided by people caring for patients with AD, noted a statistically significant benefit of 37% compared to placebo.4 The adjusted mean change from baseline at 18 months in the ADCS-MCI-ADL score was −3.5 in the lecanemab group and −5.5 in the placebo group (difference, 2.0; 95% CI, 1.2 to 2.8; P<0.001).4 The ADCS MCI-ADL assesses the ability of patients to function independently, including being able to dress, feed themselves and participate in community activities. The most common adverse events (>10%) in the lecanemab group were infusion reactions, ARIA-H (combined cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis), ARIA-E (edema/effusion), headache, and fall.4 Eisai has submitted applications for approval of lecanemab in 14 countries and regions, including the European Union (EU). Eisai has also submitted the Supplemental Biologics License Application (sBLA) for monthly lecanemab intravenous (IV) maintenance dosing to the U.S. FDA. 2. About the Collaboration between Eisai and Biogen for AD Eisai and Biogen have been collaborating on the joint development and commercialization of AD treatments since 2014. Eisai serves as the lead of LEQEMBI development and regulatory submissions globally with both companies co-commercializing and co-promoting the product and Eisai having final decision-making authority. 3. About the Collaboration between Eisai and BioArctic for AD Since 2005, Eisai and BioArctic have had a long-term collaboration regarding the development and commercialization of AD treatments. Eisai obtained the global rights to study, develop, manufacture and market LEQEMBI for the treatment of AD pursuant to an agreement with BioArctic in December 2007. The development and commercialization agreement on the antibody LEQEMBI back-up was signed in May 2015. 4. About Lemborexant (DAYVIGO®) Lemborexant, an orexin receptor antagonist, is Eisai's in-house discovered and developed small molecule that inhibits orexin neurotransmission by binding competitively to the two subtypes of orexin receptors (orexin receptor 1 and 2). In individuals with normal daily sleep-wake rhythms, orexin signaling is believed to promote periods of wakefulness. In individuals with sleep-wake disorders, it is possible that orexin signaling which regulates wakefulness is not functioning normally, suggesting that inhibiting inappropriate orexin signaling may enable initiation and maintenance of sleep. It has been approved for the treatment of insomnia in over 15 countries including Japan, the United States, Canada, Australia and countries in Asia. SOURCE Eisai Inc.