Although many of Alzheimer's disease-targeting novel drugs are in development, the market is struggling to receive the health authority approval with troubles found during efficacy validation

To this date, multinational pharmaceutical companies have initiated investigation on antibody agents targeting a number of therapeutic targets, such as amyloid-β (Aβ), Tau protein and ApoE4. But they all halted their clinical trials with the same reason.

And academic scholars are also skeptical that such antibody drugs for a single target mechanism would result in significant benefit in treating Alzheimer's disease, which has complicated pathophysiology.

# The U.S. Food and Drug Administration (FDA) Advisory Committee (AdCom) has reportedly disapproved Biogen and Eisai Pharmaceuticals’ investigational antibody targeting amyloid aducanumab in preparation for a New Drug Application (NDA).

"Two cases of submitted clinical data insufficient to prove treatment efficacy"

Biogen’s analysis on two Phase III studies—EMERGE and ENGAGE—were the controversial evidences assessed during the clinical evaluation.

After comparing EMERGE and ENGAGE data, the AdCom voted eight-to-one against on aducanumab, claiming they could not confirm concrete enough clinical evidence to validate the efficacy.

Biogen has actually halted both EMERGE and ENGAGE studies in March last year based on the outcomes of a futility analysis.

But the brake on the NDA was listed after the company gave a presentation at a major academic conference and announced its plan to submit Biologics License Application (BLA) to FDA in late last year as they acquired more analytical data after they decided to halt the studies in March.

When Eisai in partnership with Biogen unveiled a new set of analysis arguing a high dose of aducanumab demonstrates significant slowing of decline in cognition and in the EMERGE study, FDA announced it would resume reviewing the marketing approval.

After collecting a large-scale data on 2,066 out of 3,285 patients, who continued the treatment for 18 months after participating in the original trial, aducanumab resulted in statistically meaningful decrease in clinical progression of Alzheimer's disease.

The retrospective analysis on EMERGE study found aducanumab met its primary endpoint, where the patients treated with high dose aducanumab showed a statistically significant reduction of clinical decline from baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores at 78 weeks. Compared to the placebo group, the investigational drug group was improved by approximately 23 percent.

The study’s secondary endpoints were also met as the clinical decline continued to lessen. The aducanumab group, in comparison to the placebo group, improved the Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale scores by 15 percent and 27 percent, respectively. Also the scores on Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 Items (ADAS-Cog 13) and Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory Mild Cognitive Impairment Version (ADCS-ADL-MCI) marked 27 percent and 40 percent higher than the placebo group, respectively.

However, AdCom official stated, “It is still difficult to confirm the treatment’s benefit with the company raising the dose of the investigational drug higher than what is mentioned in the initial clinical protocol.”

Competition heightens among Alzheimer’s disease targeting drugs, experts reserve judgment on single target mechanism

# In the current Alzheimer's disease treatment pipeline market, a wide array of antibody agents targeting Aβ, Tau protein and ApoE4 are in development to treat patients with Alzheimer's disease.

Regardless, most of these drugs are not targeting the patients with Alzheimer's disease, but focusing on customizing the treatment to patients with a specific mutation.

An academic society reported clinical trials are now actively investigating novel drugs targeting Aβ and Tau protein for Alzheimer’s disease treatment. However, Aβ-targeting drugs only brought disappointment to many of multinational companies, although it was considered the most potent candidate.

Roche failed to meet the endpoints in late phase clinical trial on crenezumab targeting Aβ in last February and March, and Biogen and Eisai also had to quit the last Phase III trial on aducanumab.

The Aβ-targeting drug development seems to have slowed down noticeably at the moment, while Eli Lilly and MSD have also announced stopping the investigation on beta amyloid cleaving enzyme (BACE) inhibitors. And AstraZeneca, Jansen, MSD and Roche are on a same boat as they all announced they have closed their clinical trials on the drug due to reports of adverse reaction and issues with efficacy in late-phase studies.

Reviewing all the news, the academic scholars are more reserved on their opinions on developing Alzheimer's disease targeting treatments.

Suk Seung-han, a professor of neurology at Wonkwang University Sanbon Hospital, noted, “The academic scene agrees that accumulated Aβ and Tau protein expressing toxicity effect in nerve cells cause functional problems like killing of nerve cell and deteriorating cognitive function. But the problem is that some patients, according to their medical records so far, abnormally show deteriorating cognitive function regardless of the low level of accumulated Aβ and Tau protein.”

The professor added, “Now the academia is saying there is a high possibility of other risk factors like cerebrovascular lesion and other complications that could develop into dementia in patients, besides Aβ and Tau protein. We are still not convinced that dementia or decline in cognitive function can be prevented by simply hindering the mechanism of a specific factor.”