Unsure efficacy of Alzheimer's drug aducanumab

KDA focuses on identifying the drug's clinical utility in its Annual Fall Conference

“Cost is key”…administration of aducanumab positively reviewed due to limited options in market

The Korean Dementia Association has reviewed the clinical potential of aducanumab (Aduhelm), the first new drug for Alzheimer's disease to be introduced to the field in 18 years.

 

With the efficacy of the drug under constant debate, and being barely approved for its effect in reducing surrogate biomarkers such as amyloid reduction in Korea and turned down in Europe, KDA’s position is that verification over time is required to confirm the drug’s actual effect.

 

On the 16th, KDA held its KDA Annual Fall Conference at the Baekbeomgimgu Memorial Hall.

 

At the event, held a panel discussion session with 4 members including KDA Chair Dong-Won Yang and KDA President Ae Young Lee.

 

In June 2021, the US FDA granted conditional approval for aducanumab as a treatment for Alzheimer’s.

 

Aducanumab, which is a monoclonal antibody developed to target the mechanism of Alzheimer’s Disease, had become the first new drug to be approved for Alzheimer’s since 2003.

 

As abnormal accumulation and aggregation of beta-amyloid plaques are reported in the brains of patients with Alzheimer’s, the widely-accepted theory in the field was that these protein buildups (plaques) generate neurotoxins and gradually deteriorate the cognitive function of the brain.

 

Aducanumab was developed to remove this plaque, and although it is not a cure, its effect in was in slowing down cognitive decline in patients was recognized.

 

But still, there is an ongoing debate on whether the drug is ‘clinically effective’ in academia, including among FDA’s internal advisors.

 

As the drug failed to demonstrate efficacy in the clinical trial that used the change from baseline on the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) as the scale, experts judged that it is difficult to definitively acknowledge the drug’s effect only with the surrogate endpoint that demonstrated reduced amyloid accumulation.

 

Fully aware of such controversy during its review, the FDA had set a condition upon approval that Biogen will have to conduct post-approval studies to verify the treatment’s anticipated clinical benefit in addition to the amyloid PET results.

 

However, the EMA refused to grant marketing authorization for the drug.

 

Through a statement, KDA had announced, “Despite much controversy, approval of aducanumab is in itself encouraging news for patients, clinical doctors and researchers in the field,” and stressed that the association will make efforts to rigorously verify the drug’s effect with science in the future to members while sharing relevant information.

 

The panel discussion also focused on whether the amyloid plaque removal mechanism translates to real clinical efficacy.

 

Jae Hong Lee, Professor of Neurology at Seoul Asan Medical Center, said, “As the drug wasn’t able to reach the primary efficacy endpoint of the trial, it is difficult to readily embrace the FDA's approval result.

 

However, I believe the FDA approved the new drug despite headwinds as the promise of a cure with new drugs in development is a long way off.

 

Lee added, “Considering the strict standards that have been applied to new drugs for Alzheimer's disease so far, the drug was difficult to be approved.

 

To some, the CDR-SB improvement in patients who were administered the 10mg high-dose over 14 times in the post-analysis may seem far-fetched.” “Results show only 0.1% of the patients passed the final clinical review.

 

This is an unconventional and proactive attitude on the FDA’s part when considering FDA’s traditional approval standards.

 

In the ENGAGE trial, the drug failed to demonstrate its clinical efficacy but demonstrated a reduction in biomarkers, therefore, whether the improvement in biomarkers will bring clinical effect needs to be seen,” said Lee, warning caution over overinterpretation of the trial results.

 

In other words, although clinical improvement can be expected due to the reduced biomarker effects demonstrated by amyloid and tau protein, Lee believes the time is needed to verify the efficacy of the drug.

 

KDA Chair Dong-Won Yang said, “It is quite interesting that the drug continued to reduce amyloid plaques and tau in up to 1 and 2 years after high-dose administration.

 

We need to recognize its effect in removing amyloid plaques.” Sang-Yoon Kim, Professor of Neurology at Seoul National University Bundang Hospital said, “The drug does have an amyloid reduction effect, but its clinical effect may differ by months.

 

Also, the tau protein reduction was observed, but due to the small number of patients, we would need to wait longer to observe its actual effect," he said.

 

KDA President Ae Young Lee limited the drug’s utility in terms of its side effects.

 

ARIA (amyloid-related imaging abnormalities) more commonly occurred in the aducanumab administered group (43%).

 

In addition, ARIA-E occurred in about 50% of the 7th dose and 90% of the 12th dose of aducanumab.

 

President Lee said, “With over 40% of patients administered the high-dose experiencing ARIA, observation according to administration period and the number of doses will be needed.

 

As the occurrence rate differs by up to 7 times in ApoE E4 carriers, we need to play caution in using the drug for treatment.” Professor Kim said, “ Patients were recruited under very strict standards for the clinical trial, to the extent that patients with other diseases were excluded from the trial.

 

This is very different from the characteristics of patients in the actual clinical environment.

 

As there is a possibility of side effects in case patients have heart conditions or other diseases, a guideline for its administration needs to be set.” Kim added, “Since the effect has been confirmed in a specific patient group in the trial if the drug is introduced in Korea, we would also need to strictly select a patient group in consideration of the side effects and effects in line with the clinical trial.

 

We need to leave the decision on whether to administer the drug at the discretion of each clinician,” However, considering the current treatment environment in which there is no suitable new drug, most HCPs have shown a positive response to ‘making an attempt’ with aducanumab.

 

The larger issue is its price, which costs tens of millions of won.

 

Professor Lee said, “Price of aducanumab fell from the ₩65 million early on to ₩25-30 million currently.

 

If the price becomes more reasonable, I plan to attempt administering the drug to patients who are less likely to develop ARIA and see an effect.

 

Chair Yang said, “I believe the drug may be of help as I've seen many patients whose condition deteriorates with amyloid accumulation.

 

It would be great if we can use the drug in the early stages of the disease, but we need to gradually increase the dose with continuous MRI monitoring due to the possibility of ARIA."