Anti-Amyloid Therapy

Question 1

What are the three types of anti amyloid therapy?

Answer 1

1. Aducanumab
2. Lecanemab
3. Donanemab

Question 2

How do anti amyloid therapies work?

Answer 2

Monoclonal antibodies
Disease modifying
Work to clear beta amyloid at different points in the pathway of formation of plaques

Question 3

Where do each of the anti amyloid drugs target?

Answer 3

1. Aducanumab - AB fibrils
2. Lecanemab - protofibrils
3. Donanemab - plaques only

Question 4

What populations did the anti amyloid studies investigate?

Answer 4

MCI or mild AD
Amyloid positivity needed to be proven on PET or CSF
Ages 50-90 depending on study

Question 5

What were positive outcomes of aducanumab study?

Answer 5

EMERGE ONLY (not ENGAGE)
Primary outcome
Decrease of CDR-SB score
Secondary outcomes
1. MMSE
2. ADAS-Cog
3. ADCS-ADL-MCI

Question 6

What were positive outcomes of lecanemab study?

Answer 6

Decrease in CDR-SB score
Secondary
Amyloid burden on PET
ADAS-Cog decrease
ADCS-MCI-ADL increase
ADCOMS

Question 7

What were positive outcomes of donanemab study?

Answer 7

Least squares mean change in iADRs score

Secondary
CDR-SB slowed progression
ADCS-IADL slowed progression
ADAS-Cog slowed progression
Dec Amyloid burden on PET
Dec Tau burden plasma (not on PET)

Question 8

What was the main side effect of anti amyloid therapy?

Answer 8

ARIA = amyloid relating imaging abnormalities
These can occur as part of normal AD pathology but also with treatment
Only seen on MRI
Other most common AE was infusion reaction

Question 9

What are the two types of ARIA?

Answer 9

Hemorrhage - microhemorrhages and superficial hemosiderosis
Edema - parenchymal edema and sulcal effusion

Question 10

What were identified risk factors for ARIA?

Answer 10

APOE4 carriers
Earlier in treatment course
High dose of drug (only ARIA-E)
Antithrombotic use (only ARIA-H)
CAA (only ARIA-H)

Question 11

What symptoms are associated with ARIA?

Answer 11

Usually transient and asymptomatic (ARIA-H more often asymptomatic)

Headache
Dizzy
Visual changes
Confusion
Seizure
Rarely death

Question 12

What do you do to manage ARIA?

Answer 12

If minor or asymptomatic: monitor with imaging, usually 1x/month
If mod-sev or symptoms: stop tx, monthly imaging, if resolves on imaging AND clinically restart tx
IV steroids have been used for edema

Question 13

Which of the 3 anti amyloid drugs has the least ARIA?

Answer 13

Lecanemab
Donanemab
Aducanumab

Question 14

What are 4 arguments against the approval of aducanumab?

Answer 14

One of the trials did not have significant findings
Surrogate end point was beta amyloid clearance, not clinically meaningful
Signifiant adverse effects
Poor cost effectiveness ratio

Question 15

What are general concerns/criticisms regarding anti amyloid therapies?

Answer 15

1. Significant costs
2. Risk of adverse events
3. Lack of diversity of study population particularly with regards to race
4. Amyloid is not the only change in NDD, there is also tau and possibly unknown pathologies
5. Need for biomarker testing (CSF or PET)
6. Need to regular infusions (q2-4 weeks)
7. Need for regular MRI imaging

Question 16

What were the inclusion criteria for the lecanemab CLARITY study?

Answer 16

1. 50-90 yo
2. MCI due to AD or mild AD based on NIA-AA criteria
3. Objective impairment in episodic memory (min 1 SD below age adjusted mean in Wechsler Memory Scale iV-Logical Memory)
4. Amyloid positivity on PET or CSF

Question 17

What is the mechanism of ARIA?

Answer 17

Due to fragility of blood vessels and leakage of proteinaceous fluid (E) and eryhrocytes/heme products (H) due to therapeutic effects of monoclonal antibodies