– 51% of No Tau / Low Tau Patients Showed Improved Cognition and Function Over Three Years; Only Lecanemab Has Clinical Data in No Tau / Low Tau Patient Group
– Clinical Data and Biomarkers Show Alzheimer’s Disease Does Not Stop Progressing After Plaque Clearance. Lecanemab’s Dual Action Supports Neuronal Function by Clearing Highly Toxic Protofibrils that Continue to Cause Neuronal Injury and Death After Rapid Plaque Clearance
– Lecanemab Slows Tau Spread Across All Brain Regions
PHILADELPHIA, July 30, 2024 /PRNewswire/ — Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) and Biogen Inc. (Nasdaq: BIIB, Headquarters: Cambridge, Massachusetts, United States, CEO: Christopher A. Viehbacher, “Biogen”) announced today that the latest findings for lecanemab-irmb (U.S. brand name: LEQEMBI®), an anti-amyloid beta (Aβ) protofibril* antibody for the treatment of early Alzheimer’s disease (AD), were presented at the Alzheimer’s Association International Conference (AAIC) 2024, held in Philadelphia, USA, and virtually. Dual-acting lecanemab is the only early AD treatment widely available to support neuronal function by clearing the highly toxic protofibrils that continue to cause neuronal injury and death even after plaques have been cleared from the brain. The presentation slides for the two scientific sessions on lecanemab at the AAIC will be available on the Eisai Co. Ltd. Investor Page by 7:00 p.m. on July 30th EDT.
Three Years of Continuous Lecanemab Treatment Reduced Clinical Decline by -0.95 on CDR-SB Showing Continued Clinically and Personally Meaningful Benefit for Early AD Patients
Even After Plaque Clearance, AD Continues to Progress When Treatment is Stopped
Experience the full interactive Multichannel News Release here: https://www.multivu.com/players/English/9282551-eisai-leqembi-clinical-data-aaic-2024-alzheimers/
Three Years of Continuous Lecanemab Treatment Reduced Clinical Decline by -0.95 on CDR-SB Showing Continued Clinically and Personally Meaningful Benefit for Early AD PatientsClarity AD was a global Phase 3 placebo-controlled, double-blind, parallel-group, randomized study in 1,795 people with early AD (Lecanemab group: 10 mg/kg bi-weekly IV treatment: 898, placebo group: 897). 95% of patients who completed the core study (18 months) chose to continue in the open-label extension study (OLE). In the Clarity AD core study, the mean change from baseline between the lecanemab treated group and the placebo group was -0.45 (P=0.00005) on the primary endpoint of the Clinical Dementia Rating-Sum of Boxes (CDR-SB) global cognitive and functional scale. Over three years of treatment across the core study and OLE, lecanemab reduced cognitive decline on the CDR-SB by -0.95 compared to the expected decline based on the Alzheimer’s Disease Neuroimaging Initiative (ADNI)** group.1 A change from 0.5 to 1 on the CDR score domains of Memory, Community Affairs and Home/Hobbies is the difference between slight impairment and loss of independence, such as people’s ability to be left alone, remember recent events, participate in daily activities, complete household chores, function independently and engage in hobbies and intellectual interests.2,3
Safety MattersNo new safety findings have been observed with continued lecanemab treatment over three (3) years. Most Amyloid-related imaging abnormalities (ARIA) occurred in the first six months of treatment. After the first six months, ARIA rates are low and similar to ARIA rates on placebo. Most patients who had ARIA had CDR-SB assessments after the event. Sensitivity analyses showed ARIA had no impact on cognition or function. From these results ARIA was not associated with accelerated long-term progression.1 As stated in the FDA product label, the incidence and timing of ARIA vary among treatments.4
More than 50% of Patients Who Started Treatment in the Earliest Stage of AD Continued to Show Improvement After Three Years of Lecanemab TreatmentThe Clarity AD study included an optional tau PET substudy and used the tau PET probe MK6240 to identify patients with no tau or a low accumulation of tau in the brain. As tau begins to accumulate in the brain, cognition and function start to decline; therefore, patients with no tau or low tau in the brain represent an early stage of AD. After three years of lecanemab treatment, 59% of these patients (24/41) showed improvement or no decline, and 51% (21/41) showed improvement from baseline on the CDR-SB. On the ADAS-Cog14 measurement scale, 63% of patients showed improvement or no decline and 61% showed improvement. On the ADCS MCI-ADL, 63% of patients showed improvement or no decline and 59% showed improvement. This suggests that earlier initiation of treatment with lecanemab may have a significant positive impact on disease progression and may provide continued benefits to patients with early AD over the long-term.1
Even After Plaque Clearance, AD Continues to Progress When Treatment is StoppedStudy 201 is a multicenter, double-blind, placebo-controlled, Phase 2b trial conducted in 856 patients with early AD. Appropriate patients participated in the OLE after an off-treatment period of 9-59 months (mean: 24 months) following the 18-month core study. During the off-treatment period lecanemab’s clinical effect was maintained but the rate of decline (slope) in patients who stopped therapy reverted back to the rate of decline in patients on placebo as measured by CDR-SB. This indicates that even after Aβ plaque is removed, AD continues to progress, and reverts to the placebo rate of decline when treatment is stopped.1
After Plaque Removal, Dual-Acting Lecanemab Continues to Positively Impact Biomarkers Over the Course of TreatmentThe key AD fluid biomarkers Aβ42/40, pTau181, pTau217, and glial fibrillary acidic protein (***GFAP) are more sensitive indicators of amyloid and tau development than Amyloid PET and have been shown to re-accumulate at a faster rate when treatment is discontinued. Modeling data from the Study 201 (Phase 2), Clarity AD (Phase 3) and respective OLE studies showed that the half-life of the treatment effect on the fluid biomarkers plasma Aβ42/40 ratio, pTau181, and GFAP are lost within 0.5 year, 1.6 years and 1.7 years, respectively, while the half-life of the treatment effect on amyloid plaque is gradually lost in 12.1 years. When lecanemab treatment was resumed in the Study 201 OLE after off-treatment period, fluid biomarkers Aβ42/40 ratio, pTau181, pTau217 and GFAP improved. These results suggest that AD continues to progress when treatment is stopped, even after plaque has been cleared. Patients continue to benefit by remaining on treatment as lecanemab maintains improvement in the fluid biomarkers of amyloid pathophysiology.1
Lecanemab’s Dual Action on Protofibrils and Plaques Impacts Amyloid and Slows Tau Spread, Offering Patients a Continuous, Long-Term Treatment for this Chronic and Progressive Disease Lecanemab is the only widely available early AD treatment that offers a dual mechanism of action designed to selectively target highly toxic protofibrils in addition to amyloid plaques. Protofibrils accumulate early in the AD brain and lead to nerve cell function loss, abnormal nerve processes, inflammation, and memory loss. In non-clinical studies, antibodies against protofibrils prevented protofibril-mediated neuronal dysfunction and memory loss.5 Lecanemab preferentially binds to toxic protofibrils with the highest affinity. After rapidly clearing plaque and existing protofibrils, lecanemab continuously clears the protofibrils that continue to develop and damage neurons.1 Protofibrils also play a role in tau spread.5 In the tau PET substudy, continuous lecanemab treatment slowed the rate of increase in tau accumulation across all brain regions as measured by tau PET.6 CSF MTBR-tau243 has high correlation with tau PET and increases with the progression of AD pathology. Treatment with lecanemab slows the increase in CSF MTBR-tau243. Additionally, lecanemab improved pTau217 and other biomarkers related to neuroinflammation and neurodegeneration. This indicates a potential disease-modifying effect on tau pathophysiology.7
Eisai serves as the lead for lecanemab’s development and regulatory submissions globally with both Eisai and Biogen co-commercializing and co-promoting the product and Eisai having final decision-making authority.
*Protofibrils are thought to be the most toxic Aβ species that contribute to brain damage in AD and play a major role in the cognitive decline of this progressive and devastating disease. Protofibrils can cause neuronal damage in the brain, which can subsequently adversely affect cognitive function through multiple mechanisms.5 The mechanism by which this occurs has been reported not only by increasing the formation of insoluble Aβ plaques, but also by directly damaging signaling between neurons and other cells. It is believed that reducing protofibrils may reduce neuronal damage and cognitive impairment, potentially preventing the progression of AD.8
**ADNI is a clinical research project launched in 2005 to develop methods to predict the onset of AD and to confirm the effectiveness of treatments. The ADNI observational cohort represents the exact population of those in Clarity AD study; matched ADNI participants show similar degree of decline to placebo group out to 18 months.
*** Glial fibrillary acidic protein (GFAP), a marker of astroglia activation, has been proposed as a biomarker of Alzheimer’s disease (AD). GFAP expression correlates with Aβ plaque density and cerebrospinal fluid (CSF) concentration is elevated in symptomatic disease.
Please see full Prescribing Information for LEQEMBI, including Boxed WARNING.
U.S. INDICATIONLEQEMBI® [(lecanemab-irmb) 100 mg/mL injection for intravenous use] is indicated for the treatment of Alzheimer’s disease (AD). Treatment with LEQEMBI should be initiated in patients with mild cognitive impairment (MCI) or mild dementia stage of disease, the population in which treatment was initiated in clinical trials.
IMPORTANT SAFETY INFORMATION
|
WARNING: AMYLOID-RELATED IMAGING ABNORMALITIES (ARIA) Monoclonal antibodies directed against aggregated forms of amyloid beta, including LEQEMBI, can cause ARIA, characterized as ARIA with edema (ARIA-E) and ARIA with hemosiderin deposition (ARIA-H). Incidence and timing of ARIA vary among treatments. ARIA usually occurs early in treatment and is asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, rarely can occur. Serious intracerebral hemorrhages >1 cm, some fatal, have been observed with this class of medications. Apolipoprotein E ε4 (ApoE ε4) Homozygotes: Patients who are ApoE ε4 homozygotes (~15% of patients with AD) treated with this class of medications have a higher incidence of ARIA, including symptomatic, serious, and severe radiographic ARIA, compared to heterozygotes and noncarriers. Testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prescribers should discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results. Prescribers should inform patients that if genotype testing is not performed, they can still be treated with LEQEMBI; however, it cannot be determined if they are ApoE ε4 homozygotes and at higher risk for ARIA. Consider the benefit of LEQEMBI for the treatment of AD and the potential risk of serious ARIA events when deciding to initiate treatment with LEQEMBI. |
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 ABNORMALITIESLEQEMBI can cause ARIA-E and ARIA-H, which can occur together. ARIA-E can be observed on magnetic resonance imaging (MRI) as brain edema or sulcal effusions and ARIA-H as microhemorrhage and superficial siderosis. ARIA can occur spontaneously in patients with AD. With this class of medications, ARIA-H generally occurs in association with ARIA-E. Reported ARIA symptoms may include headache, confusion, visual changes, dizziness, nausea, and gait difficulty. Focal neurologic deficits may also occur. Symptoms usually resolve over time.
Incidence of ARIASymptomatic ARIA occurred in 3% (29/898) and serious ARIA symptoms in 0.7% (6/898) with LEQEMBI. Clinical ARIA symptoms resolved in 79% (23/29) of patients during the period of observation. ARIA, including asymptomatic radiographic events, was observed: LEQEMBI, 21% (191/898); placebo, 9% (84/897). ARIA-E was observed: LEQEMBI, 13% (113/898); placebo, 2% (15/897). ARIA-H was observed: LEQEMBI, 17% (152/898); placebo, 9% (80/897). No increase in isolated ARIA-H was observed for LEQEMBI vs placebo.
ApoE ε4 Carrier Status and Risk of ARIAOf the patients taking LEQEMBI, 16% (141/898) were ApoE ε4 homozygotes, 53% (479/898) were heterozygotes, and 31% (278/898) were noncarriers. With LEQEMBI, 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%). Symptomatic ARIA-E occurred in 9% of ApoE ε4 homozygotes vs 2% of heterozygotes and 1% of noncarriers. Serious ARIA events occurred in 3% of ApoE ε4 homozygotes and in ~1% of heterozygotes and noncarriers. The recommendations on management of ARIA do not differ between ApoE ε4 carriers and noncarriers.
Radiographic FindingsThe majority of ARIA-E radiographic events occurred within the first 7 doses, although ARIA can occur at any time, and patients can have >1 episode. Maximum radiographic severity of ARIA-E with LEQEMBI was mild in 4% (37/898), moderate in 7% (66/898), and severe in 1% (9/898) of patients. Resolution of ARIA-E on MRI occurred in 52% of patients by 12 weeks, 81% by 17 weeks, and 100% overall after detection. Maximum radiographic severity of ARIA-H microhemorrhage with LEQEMBI 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) of patients. With LEQEMBI, the rate of severe radiographic ARIA-E was highest in ApoE ε4 homozygotes (5%; 7/141) vs heterozygotes (0.4%; 2/479) or noncarriers (0%; 0/278). With LEQEMBI, the rate of severe radiographic ARIA-H was highest in ApoE ε4 homozygotes (13.5%; 19/141) vs heterozygotes (2.1%; 10/479) or noncarriers (1.1%; 3/278).
Intracerebral HemorrhageIntracerebral hemorrhage >1 cm in diameter was reported in 0.7% (6/898) with LEQEMBI vs 0.1% (1/897) with placebo. Fatal events of intracerebral hemorrhage in patients taking LEQEMBI have been reported.
Concomitant Antithrombotic Medication:
In Clarity AD, 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) in patients taking LEQEMBI with a concomitant antithrombotic medication at the time of the event vs 0.6% (3/545) 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) vs none in patients receiving placebo. 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 Clarity AD 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). The presence of an ApoE ε4 allele is also associated with cerebral amyloid angiopathy. Caution should be exercised when considering the use of LEQEMBI in patients with factors that indicate an increased risk for intracerebral hemorrhage and in patients who need to be on anticoagulant therapy.
ARIA Monitoring and Dose Management GuidelinesObtain a recent baseline brain MRI prior to initiating treatment with LEQEMBI and prior to the 5th, 7th, and 14th infusions. Enhanced clinical vigilance for ARIA is recommended during the first 14 weeks of treatment with LEQEMBI. Depending on ARIA-E and ARIA-H clinical symptoms and radiographic severity, use clinical judgment when considering whether to continue dosing or to temporarily or permanently discontinue LEQEMBI. If a patient experiences ARIA symptoms, 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.
HYPERSENSITIVITY REACTIONSHypersensitivity reactions, including angioedema, bronchospasm, and anaphylaxis, have occurred with LEQEMBI. 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 (IRRs)IRRs were observed—LEQEMBI: 26% (237/898); placebo: 7% (66/897)—and the majority of cases with LEQEMBI (75%, 178/237) occurred with the first infusion. IRRs were mostly mild (69%) or moderate (28%) in severity. IRRs resulted in discontinuation of LEQEMBI in 1% (12/898). Symptoms of IRRs 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 IRR, the infusion rate may be reduced or the infusion may be discontinued and appropriate therapy initiated as clinically indicated. Consider prophylactic treatment prior to future infusions with antihistamines, acetaminophen, nonsteroidal anti-inflammatory drugs, or corticosteroids.
ADVERSE REACTIONSThe most common adverse reaction leading to discontinuation of LEQEMBI was ARIA-H microhemorrhages that led to discontinuation in 2% (15/898) with LEQEMBI vs