THE AHEAD STUDY IS TESTING LECANEMAB AT THE STAGE OF PRECLINICAL ALZHEIMER'S DISEASE

2023-07-11

临床3期临床结果临床2期上市批准引进/卖出

SAN DIEGO, July 11, 2023 /PRNewswire/ -- Alzheimer's disease (AD) researchers increasingly believe that treating at the earliest possible stage may be key to helping combat the disease. Ongoing studies are now testing whether lecanemab can effectively delay or prevent the symptoms of disease if started even before there is evidence of cognitive impairment.

The AHEAD Study (AHEADstudy.org) is testing the effect of lecanemab in people who have no cognitive symptoms of AD but in whom biomarker tests indicate amyloid is present in the brain, known as the "preclinical" stage of AD. The AHEAD Study is the first AD trial to recruit people as young as 55 years old who are at risk of developing symptoms of AD as they get older.

On July 6, the Food and Drug Administration granted full approval to LEQEMBI (lecanemab) for the treatment of AD. Under the current FDA approval, treatment with lecanemab 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. Lecanemab is the first approved treatment shown to reduce the rate of disease progression and to slow cognitive and functional decline in adults with AD (Eisai Press Release).

Lecanemab is now fully approved to treat people who already have cognitive impairment and mild dementia (substantial memory and other thinking problems that affect daily function) due to AD. Lecanemab had previously been granted accelerated approval for demonstrating that the treatment reduced the accumulation of brain amyloid plaque (a hallmark change in the brain of a person with AD). The AHEAD Study builds on the positive results that lecanemab showed in people with mild cognitive impairment or mild dementia in the Clarity AD Study. Studies like the AHEAD Study are necessary to test if lecanemab can help stave off the memory problems caused by AD, if started before cognitive impairment is clinically evident.

"The advances in treating people who already have cognitive problems due to Alzheimer's disease are incredibly exciting, but to have the greatest impact on the public health crisis of Alzheimer's disease, we may need treatments to start even earlier," said Reisa Sperling, M.D., professor of Neurology at Harvard Medical School and co-principal investigator of the AHEAD Study. "The AHEAD Study is the first study to test whether removing amyloid plaques from the brain before symptoms are evident could be effective at preventing memory problems from the beginning."

The AHEAD Study incorporates innovative features such as screening with biomarkers in blood, novel PET imaging agents, sensitive cognitive outcome scales, dosing tailored to the level of amyloid in the brain, and recruitment approaches to ensure diverse representation.

The AHEAD Study is funded by the National Institutes of Health (NIH) and Eisai Inc., a U.S. subsidiary of Eisai Co., Ltd. (Headquarters: Tokyo), and seeks 1,165 participants from North America. The study has more than 100 study locations worldwide, including North America, Japan, Singapore, Australia, and Europe.

To learn more about the AHEAD Study, call 1-800-AHEAD-70 or to find a trial site location enrolling near you, visit AHEADstudy.org.

EDITOR: Research reported in this press release was supported by the NIH's National Institute on Aging under award numbers R01AG054029 and R01AG061848. The AHEAD Study (Clinical Trial number NCT04468659) received funding from NIH and from nongovernmental sources. The content is solely the responsibility of the researchers and does not necessarily represent the official views of the NIH.

This release discusses investigational uses of an agent and is not intended to convey conclusions about efficacy or safety. There is no guarantee that an agent will successfully complete clinical development or gain health authority approval.

CONTACT: Rachel Griffith, 202-553-8303, [email protected]

About AHEAD / Lecanemab

The AHEAD Study is made up of two different clinical trials testing lecanemab at different doses. During the study, participants will receive intravenous (IV) infusions of lecanemab tailored to their risk of developing memory loss or a placebo, an inactive substance designed to mimic the appearance of the drug. At different points in the study, participants have a PET scan (or Positron Emission Tomography brain scan) to look at amyloid and tau (another protein) in the brain. The PET scan takes pictures of participants' brains, allowing researchers to see and track changes in amyloid and tau levels.

About Lecanemab

Lecanemab is a humanized monoclonal antibody for Alzheimer's disease (AD) that is the result of a strategic research alliance between Eisai and BioArctic AB (Headquarters: Sweden). Lecanemab selectively binds to neutralize and eliminate soluble, toxic Aβ aggregates (protofibril) that are thought to contribute to the neurodegenerative process in AD. As such, lecanemab may have the potential to have an effect on disease pathology and to slow down the progression of the disease. Eisai obtained the global rights to study, develop, manufacture, and market lecanemab for the treatment of AD pursuant to an agreement concluded with BioArctic in December 2007. Results from the global clinical Phase III study (Clarity AD) of lecanemab in early AD were recently announced. Now also in a Phase III trial (AHEAD 3-45) for preclinical AD, Lecanemab is being jointly developed by Eisai and Biogen Inc.

About the Alzheimer's Clinical Trials Consortium

The Alzheimer's Clinical Trial Consortium (ACTC) is a state-of-the-art infrastructure network established with funding by the NIA to support the conduct of clinical trials across the continuum of Alzheimer's Disease (AD). The ACTC leverages the depth and breadth of AD clinical research teams at USC, Harvard, and the Mayo Clinic, as well as the considerable experience of investigators at 35 expert AD trial sites to provide an optimal infrastructure, utilizing centralized resources and shared expertise, to accelerate the development of effective interventions for Alzheimer's disease and related disorders (ADRD).

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% 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 reactions leading to discontinuation of LEQEMBI was ARIA-H microhemorrhages that led to discontinuation in 2% (15/898) of patients treated with LEQEMBI compared to

Please see full Prescribing Information

for LEQEMBI, including Boxed WARNING.

SOURCE Alzheimer's Clinical Trials Consortium