Aducanumab - First FDA Approved Therapy for Treating Alzheimer’s Disease

Overview:

Alzheimer's disease is prevalent among elderly individuals and is responsible for memory loss and dementia. It gradually worsens over time and significantly impacts their ability to lead a fulfilling life with autonomy. Aducanumab is a breakthrough as the first therapy that modifies the course of Alzheimer's disease (AD). However, since it only targets a specific aspect of AD's pathogenesis, there is a need for drugs that can act on multiple targets. Furthermore, it is crucial to continue the search for preventative measures, validated plasma-based tests, and more effective, safe, convenient, and affordable drugs for AD.

Despite significant advances in AD drug research and development, a cure for AD remains elusive. Most AD drugs focus on reducing the disease's symptoms rather than targeting its underlying cause. Aducanumab, a monoclonal antibody that targets both soluble (β-amyloid oligomers) and insoluble aggregates of β-amyloid proteins (fibrils and β-amyloid plaques), is the first disease-modifying agent approved by the FDA for the treatment of AD.

How Does Aducanumab Work?

Aducanumab is a medication that is the first to target what is believed to be the underlying cause of Alzheimer's disease. This drug works by eliminating clumps of beta-amyloid plaques, which are toxic proteins believed to destroy neurons in the brain, leading to cognitive decline. Aducanumab, a monoclonal antibody (MAB), stimulates the immune system to target and break down beta-amyloid plaques that are common in people with dementia. Aducanumab does not reverse the disease's progression or cure the disease for those who have already developed symptoms.

While Aducanumab has been shown to break down the amyloid plaques associated with Alzheimer's disease, it has yet to demonstrate clinically significant slowing of cognitive declines, such as wandering or getting lost, trouble handling money and paying bills, memory loss, taking longer to complete normal daily tasks, repeating questions, and personality and behavior changes.

Uses:

• Alzheimer's Disease- Aducanumab is prescribed to reduce amyloid-beta plaque, a protein found in the brain of individuals with Alzheimer's disease. Alzheimer's is a brain disease that gradually destroys a person's memory and ability to think, learn, communicate, and perform daily activities.

• Cognitive Impairment- Aducanumab is used to treat individuals with mild dementia or mild cognitive impairment (MCI). Mild cognitive impairment (MCI) is characterized by a cognitive decline that is noticeable to themselves and others but not severe enough to interfere with daily activities or independence.

Dosage:

• This drug is indicated for the treatment of Alzheimer's disease and is administered as an intravenous infusion every four weeks, with at least 21 days between infusions. In clinical trials, treatment was initiated in patients with mild cognitive impairment or mild dementia stages of the disease.

• Safety and effectiveness data for initiating treatment at earlier or later stages of the disease are not available.

• The dosing titration schedule is as follows: Infusions 1 to 2 at 1 mg/kg Aducanumab intravenously every four weeks, infusions 3 to 4 at 3 mg/kg Aducanumab intravenously every four weeks, infusions 5 to 6 at 6 mg/kg Aducanumab intravenously every four weeks, and infusion 7 and beyond at 10 mg/kg Aducanumab intravenously every four weeks.

Warning:

• ARIA (amyloid-related imaging abnormalities) can be observed on brain imaging as ARIA-E, characterized by brain edema or sulcal effusions, or ARIA-H, which can be visualized as microhemorrhage and superficial siderosis.

• A brain MRI should be obtained prior to initiating treatment due to the potential development of ARIA (amyloid-related imaging abnormalities) to ensure safe use.

• During clinical studies, ARIA was present in 24 percent of subjects who demonstrated radiographic ARIA, with symptoms including headache, confusion, delirium, altered mental status, disorientation, dizziness, vision abnormalities, and nausea, with headache being the most common (13 percent).

• ARIA primarily occurred during the initial titration of therapy for the first eight doses. Patients showing signs of ARIA should be evaluated thoroughly and receive a brain MRI to determine severity before continuing treatment.

For Patients:

Learn About Alzheimer's Disease

Alzheimer's disease is a progressive condition that can lead to losing the ability to communicate and respond to the surroundings. The disease affects specific regions of the brain that control language, memory, and thought, which can significantly impact an individual's daily activities. Alzheimer's disease is not a typical aspect of aging, and memory problems are typically the first indications of the condition and related dementias. Apart from memory problems, a person with Alzheimer's disease symptoms may experience the following:

• Memory loss interferes with daily activities, such as forgetting familiar places or repeating questions.

• Difficulty managing daily financial activities.

• Struggles to complete routine tasks at work, home, or leisure.

• Poor or reduced judgment.

• Unable to find objects or misplace them..

• Change in mood and personality.

Consulting with a healthcare provider is essential in identifying whether the symptoms are related to Alzheimer’s disease or a more treatable condition, such as vitamin deficiency or medication side effects. Obtaining an accurate diagnosis early on provides an opportunity to plan and prepare for financial and care needs and consider enrolling in clinical trials. Medical management can improve the quality of life for those with the disease and their caregivers. Treatment typically focuses on maintaining brain health, managing behavioral symptoms, and slowing or delaying the progression of the disease.

Learn More About Aducanumab

Before Starting Aducanumab:

1. Inform the doctor if there is an allergy to Aducanumab, any other medications, or any ingredients contained in Aducanumab. It is advisable to review the medication guide or speak with the pharmacist for a comprehensive list of ingredients.

2. Discuss with the doctor and pharmacist all other ongoing prescription and non-prescription medications, vitamins, herbal products, and nutritional supplements or intend to take. The physician may need to adjust the medication doses or closely monitor the patient for possible side effects.

3. Inform the doctor if there is a history of medical conditions or if currently experiencing any.

4. If a woman is pregnant, planning to become pregnant, or is breastfeeding, inform the physician.

Why and When to Switch to Aducanumab?

Aducanumab is a monoclonal antibody that targets amyloid beta (Aβ) plaques in the brain, which are thought to contribute to the development of AD and are indicated for the treatment of Alzheimer's disease (AD).

Switching to Aducanumab may be considered for patients with MCI or mild dementia stages of AD who have evidence of Aβ plaques in the brain and who have not experienced significant cognitive decline. Aducanumab has been shown to reduce the number of Aβ plaques in the brain, which may slow the progression of cognitive decline in some patients.

How Effective Is Aducanumab?

Aducanumab’s effectiveness has been a topic of debate. The FDA approved the drug under the accelerated approval pathway, which allows for approval of drugs for serious conditions based on a clinical benefit. In the case of Aducanumab, the surrogate endpoint was the reduction of amyloid beta plaques in the brain, which is thought to be a biomarker for Alzheimer's disease.

Clinical trials of Aducanumab have shown mixed results in terms of its effectiveness. In a subgroup analysis of one of the trials, patients who received the highest dose of the drug over a longer period of time found a reduction in cognitive decline compared to those who received a placebo.

Things to Tell Physicians Before They Prescribe Aducanumab:

• Medical History: Discuss the medical history with the doctor. Inform them about any past or current medical conditions, as well as any medications that are ongoing.

• Potential Risks and Benefits: Discuss the potential risks and benefits of taking Aducanumab with the doctor, including the possibility of serious side effects such as bleeding, allergic reactions, or brain swelling.

• Clinical Trial Outcomes: Discuss the outcomes of the clinical trials of Aducanumab, including the study design, the populations studied, and the results.

• Brain Imaging: Discuss the importance of regular brain imaging to monitor for any changes or abnormalities while taking Aducanumab.

• Other Treatment Options: Discuss lifestyle changes, other medications, and other therapies that may be available to treat the condition.

Starting Aducanumab

How to Take Aducanumab?

The duration of the administration of Aducanumab through intravenous infusion is 45 to 60 minutes. The infusion can be done at hospitals or infusion therapy centers, and it is required to be given via IV route. This treatment is typically done every four weeks.

• A healthcare professional will administer the drug through an intravenous route in a hospital or clinic setting.

• Before the infusion, the patient may need to have certain medical tests to make sure it is safe to receive Aducanumab.

• The infusion typically takes about one hour to complete. During the infusion, the patient will be monitored closely by healthcare professionals to make sure they do not have an adverse reaction to the medication.

• After the infusion is complete, the patient will need to be observed for a period of time to monitor for any side effects.

• Aducanumab is typically administered once a month.

What Are the Precautions to Take After Starting Aducanumab?

After starting Aducanumab, there are several things to do to ensure the best possible outcome and reduce the risk of side effects.

• Attend All Scheduled Appointments: It is important for the patient to attend all appointments with the healthcare professional as recommended. This will allow them to monitor the patient’s progress, adjust the dosage if necessary, and address any concerns.

• Report Any Side Effects: If the patient has any side effects after starting Aducanumab, report them to the healthcare provider immediately. Common side effects include confusion, headache, and falls.

• Continue With Other Treatments: Aducanumab is not a replacement for other treatments for Alzheimer's disease, such as cognitive therapy or other medications.

• Stay Mentally and Physically Active: Engage in mentally stimulating activities, such as reading or puzzles, and stay physically active with exercise as tolerated. These activities can help improve brain function and overall health.

• Follow a Healthy Diet: Overall health and brain function can be increased by the intake of a healthy diet. Talk to the healthcare provider about what foods to include or avoid.

• Keep a Track of the Progress: A journal of any changes in the symptoms or overall health after starting Aducanumab should be maintained. This can help the patient and the healthcare provider monitor the progress over time.

What Are the Side Effects of Aducanumab Therapy?

1. Amyloid-Related Imaging Abnormalities (ARIA)- Amyloid-related imaging abnormalities (ARIA) include ARIA- edema , ARIA-hemosiderin deposition (ARIA-H) microhemorrhage , and ARIA-H superficial siderosis.

2. Other Side-effects- Other reported side effects include headache, fall, diarrhea, confusion, delirium, altered mental status, or disorientation, hypersensitivity (angioedema, urticaria), and immunogenicity. While Aducanumab may cause a slight increase in serum aminotransferase, there have been no reports of liver injury associated with its use.

For Doctors:

Indication:

• Aducanumab has been approved for the management of Alzheimer's disease (AD). The drug is prescribed for mild cognitive impairment or mild dementia patients, but not for all patients with AD as previously indicated.

• Clinical trials have demonstrated a reduction in Aβ plaques in the subset of subjects with the symptoms of Alzheimer's disease, which resulted in the FDA's accelerated approval in 2021. However, the drug's continued use and full approval required further verification of its clinical benefits in post-approval studies, and its approval was met with controversy that led to the resignation of three FDA advisory board members.

• In individuals aged 65 and above with dementia, two-thirds of cases are attributed to Alzheimer's disease, and it is the sixth leading cause of mortality in the US.

• The disease is caused by the deposition of beta-amyloid protein in extracellular neuritic plaques and intracellular buildup of tau proteins resulting in neurofibrillary tangles. Its onset is gradual, leading to a decline in cognitive and behavioral abilities such as short-term memory impairment, language, attention, comprehension, and executive functioning.

• Current management involves symptomatic treatment with cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) antagonists as there is no cure or curative treatment to date.

Pharmacology:

The amyloid theory suggests that the accumulation of amyloid-beta oligopeptides is linked to the development of Alzheimer's disease. Aducanumab is a fully human IgG1 monoclonal antibody with high affinity that targets these beta-amyloid aggregates and breaks them down into smaller polypeptides or amino acids. Aducanumab has demonstrated selectivity in binding to parenchymal amyloid as opposed to vascular amyloid.

The U.S. FDA has recently approved an updated indication, indicating that aducanumab should be used in patients with mild cognitive impairment (MCI) due to AD or mild Alzheimer's dementia.

Mechanism of Action:

Aducanumab is a monoclonal antibody of the human immunoglobulin gamma 1 (IgG1) class, which is classified as an immunotherapeutic agent. This selectivity leads to a reduction in brain Aβ plaques, as well as a decrease in phosphorylated tau observed in the cerebrospinal fluid and medial temporal NFTs in a small subset of patients using tau PET.

Pharmacodynamics:

• Absorption: Aducanumab should be given monthly as an intravenous infusion at a dose of 10 mg/kg. Aducanumab is absorbed and reaches a peak concentration (Cmax) of 182.7 μg/mL after 3.0 hours, with an area under the curve (AUCinf) of 31,400 h∗μg/mL.

• Metabolism: Aducanumab is metabolized into smaller oligopeptides and amino acids for elimination. The mean clearance of Aducanumab is 0.0159 L/h and its terminal half-life is 24.8 days.

• Elimination: Aducanumab is metabolized into smaller oligopeptides and amino acids for elimination, with a mean clearance of 0.0159 L/h and a terminal half-life of 24.8 days.

Warnings and Precautions:

Amyloid-Related Imaging Abnormalities - The chances of amyloid-related imaging abnormalities (ARIA) are possible, which can be categorized into ARIA-E (edema) and ARIA-H (microhemorrhage and superficial siderosis) visible on MRI. ARIA usually manifests as temporary swelling in the brain that resolves on its own, but it can also cause symptoms such as headache, confusion, dizziness, seizures, vision changes, or nausea. ARIA is commonly observed during the first eight doses, especially during titration. Therefore, it is advised to have enhanced clinical vigilance. Safety or efficacy has not been seen in patients with localized superficial siderosis, ≥10 brain microhemorrhages, and/or a brain hemorrhage >1 cm within one year of treatment initiation.

The monitoring and management guidelines for aducanumab are as follows:

1. Dosing recommendations for patients with ARIA-E depend on the severity of clinical symptoms and radiographic findings.

2. Dosing recommendations for patients with ARIA-H depend on the type and severity of radiographic findings.

3. In cases of recurrent ARIA-E, clinical judgment should be used to determine whether to continue dosing.

4. It is recommended to have periodic monitoring with MRI and a brain MRI.

5. If a patient experiences symptoms suggestive of ARIA, clinical evaluation, including MRI if necessary, should be performed.

6. If amyloid-related imaging abnormalities are observed on MRI, a careful clinical examination and evaluation need to be conducted before continuing treatment.

Dosage Strength and Forms:

The titration schedule for aducanumab is as follows:

1. First Infusion: 1 mg/kg.

2. Second Infusion: 1 mg/kg.

3. Third Infusion: 3 mg/kg.

4. Fourth Infusion: 3 mg/kg.

5. Fifth Infusion: 6 mg/kg.

6. Sixth Infusion: 6 mg/kg.

7. Seventh infusion onwards: 10 mg/kg.

Dosage and Administration:

The solution of Aducanumab is available as a colorless to yellow, clear to opalescent liquid in single-dose vials for intravenous infusion administration. Prior to infusion, it is recommended to dilute aducanumab according to the subject's body weight with 100 mL of 0.9 percent sodium chloride injection. The diluted solution should settle at room temperature and be administered promptly, without delay. Any unused portions of the diluted solution should be disposed of properly.

Aducanumab is available in single doses of 170 mg/1.7 mL (100 mg/mL) and 300 mg/3 mL (100 mg/mL). The dosing should be gradually increased to 10 mg/kg by the seventh infusion, with each infusion given every four weeks and a minimum of 21 days between infusions.

Considerations for Administration:

There are no known contraindications for Aducanumab. Additionally, no drug-drug interactions have been reported thus far. During pivotal trials, conventional therapy for Alzheimer's disease was used, and Aducanumab can be used in conjunction with other medications used to manage the disease.

Drug Interactions:

Limited data are currently available on the potential drug interactions of Aducanumab. As a monoclonal antibody administered through intravenous infusion, it is not expected to have significant drug interactions with other medications. However, caution should be exercised when administering Aducanumab with other medications that affect the immune system or those that have potential neurotoxic effects.

Co-administration of Aducanumab with other biologic therapies or immunosuppressants may increase the risk of infections. Vaccinations with live attenuated vaccines should be avoided while on Aducanumab therapy.

Other Specifications:

• Aducanumab During Pregnancy- Insufficient information is available regarding the use of Aducanumab in pregnant women to determine potential risks of major birth defects, miscarriage, or other adverse effects on the mother or fetus.

• Lactation- There is a lack of data regarding the presence of Aducanumab in human milk, the impact on breastfed infants, or the effects on milk production. Research on other monoclonal antibodies generally suggests minimal transmission of such antibodies to human milk and limited exposure to the breastfed infant. However, the effects of this limited exposure are currently unknown.

• Aducanumab in Geriatric Patients- Aducanumab is an immunotherapeutic used for the treatment of Alzheimer's disease in geriatric patients. The medication has been studied in clinical trials involving individuals with mild cognitive impairment or mild dementia stage of the progressive neurodegenerative ailment. Geriatric patients are the primary target population for the drug, as Alzheimer's disease is a common neurodegenerative ailment in elderly individuals. Aducanumab has been shown to selectively target and bind aggregated soluble oligomers and insoluble fibril conformations of Aβ plaques in the brain.