Treatment of Alzheimer's disease, human beings still have a long, long way to go. CTAD 2021 inventory

From 9th to 12th of this month, the 14th Alzheimer's Disease Clinical Trials Conference (CTAD) was held in Boston, USA
.

Alzheimer's disease (AD) experts from all over the world gathered together to share the latest diagnosis and treatment research results and discuss future development directions
.

We have selected some important research results, let's take a look at ~ Tau-targeted antibodies: the results are not optimistic, Balazs Toth of Roche Genentech and others reported the top-line results of the Lauriet study (ROUNDTABLE 4) of the Phase 2 clinical trial
.

The purpose of the Lauriet study is to evaluate the safety and effectiveness of the anti-tau monoclonal antibody semorinemab in the treatment of patients with mild to moderate Alzheimer's disease (AD)
.

From the published data, semorinemab is a humanized anti-tau IgG4 monoclonal antibody that targets the N-terminal region of tau protein (amino acid residues 6-23)
.

The 272 patients participating in the Lauriet study were between 50-85 years old, with MMSE scores between 16-21 (inclusive), and global CDR scores of 1 or 2.
All patients were randomized 1:1 to receive intravenous injection once a month for comfort Or semorinemab (4500 mg), the treatment time is 48 weeks
.

The main study endpoint is the change of ADAS-Cog11 and ADCS-ADL
.

In the end, 241 people were included in this study
.

From the results of the study, at 49 weeks, compared with the placebo group, ADAS-Cog11 in the semorinemab treatment group decreased by 42.
2% (P=0.
0008)
.

However, ADCS-ADL, secondary clinical endpoints, or exploratory tau PET results were all negative
.

Let's take a look at the top-line data (LBR05) of the TANGO study released by Bojian
.

The TANGO study is a phase 2 clinical study of gosuranemab targeting the N-terminus of the Tau protein
.

A total of 650 patients with AD-derived MCI (303) or mild AD (347) participated in the study.
436 received gosuranemab treatment and 214 received placebo treatment
.

Unfortunately, this study showed that compared with the placebo group, gosuranemab is not effective for participants with AD-derived MCI or mild AD
.

The current research and development of gosuranemab for the treatment of AD has been terminated
.

There is also early data on a small molecule drug targeting Tau protein (LBR06)
.

The name of this drug is OLX-07010, which is a small molecule inhibitor of Tau protein self-assembly developed by Oligomerix
.

According to published preclinical research data, after oral administration of OLX-07010 in model mice, insoluble tau in the brain was significantly reduced, tau aggregates with abnormal phosphorylated tau were also reduced, and the exercise ability of mice was also improved.

.

As an oral small molecule drug, if it can succeed, it will be an important supplement to antibody drugs
.

Antibodies targeting Aβ: Does the medicine have to be used continuously? There is no dazzling data in drug research targeting Aβ
.

Shobha Dhadda of Eisai et al.
reported the Phase 2 Open Label Expansion (OLE) data (ROUNDTABLE 5) of humanized IgG1 monoclonal antibody lecanemab targeting soluble Aβ aggregates (oligomers, fibrils)
.

From the results of the study, patients tolerated lecanemab well.
Lecanemab can quickly clear the amyloid in the patient's brain, and this is also associated with the reduction of CDR-SB, ADAS-cog and ADCOMS
.

Based on clinical data with an average gap of two years (9-59 months), researchers believe that even if amyloid is widely cleared, patients with early AD require lecanemab maintenance therapy
.

In addition, OLE clinical data also showed that patients with a global CDR score of 0.
5 or 1 are more likely to benefit from lecanemab treatment
.

It is worth noting that the results of the EMBARK study of aducanumab, the first anti-Aβ antibody drug approved by the FDA, were also released (LBR02)
.

From the results of the study, those patients who received aducanumab treatment, during the time that aducanumab treatment was stopped, the reduction of amyloid plaques will also be maintained, which indicates that the effect of aducanumab on the level of amyloid plaques is long-term; but this Whether the effect will continue with the long-term interruption of aducanumab treatment needs to be studied in the real world
.

In addition, in the inter-treatment period, although the disease has progressed, the difference in clinical endpoint numbers between high-dose aducanumab and placebo remained unchanged at the end of EMERGE and ENGAGE
.

Release of new data on γ-frequency neuromodulation therapy The highly anticipated Cognito Therapeutics also brings phase 1/2 clinical data (LB11) on γ-frequency neuromodulation
.

There were 74 participants in this study, their MMSE was between 14-26 (inclusive), and all patients were randomly assigned to the treatment group and the sham stimulation group at a ratio of 2:1
.

The regimen of the treatment group was 40 Hz non-invasive audio-visual stimulation for one hour once a day
.

In the end, 53 people (72%) completed the test
.

From the perspective of efficacy, the ADCS-ADL score of the treatment group was significantly better than that of the control group.
The data provided by the researchers was that the patient's functional decline was reduced by 78% (P<0.
0003)
.

Similarly, from the perspective of changes in MMSE scores, compared with the control group, the treatment group reduced cognitive decline by 83% (P<0.
013)
.

However, the results of MADCOMs, ADAS-Cog14 and CDR-sb were not statistically different between the two groups
.

In addition, quantitative MRI analysis showed that the total brain volume loss in the treatment group was 0.
6%, while the value in the control group was 1.
5%, which means that brain atrophy was significantly reduced by 63% in 6 months (P<0.
01)
.

The adverse reaction rates of the two groups were similar, there were no serious adverse events, and no ARIA
.

Although there are certain differences with the data published at the 15th International Conference on Alzheimer's and Parkinson's Disease (AD/PD™2021), the difference is not significant
.

Looking forward to the release of updated data from Cognito Therapeutics
.

Biomarkers for the detection of early AD are constantly improving.
Compared with drugs for the treatment of AD, the biomarkers for early AD have improved more this year
.

Researchers from the University of Gothenburg and Adx Neuroscience reported the research progress of plasma pTau231 (LB01)
.

From the research results, if the results of Aβ-PET are used as a reference, the area under the curve of plasma pTau231 for early AD detection is the highest (AUC = 0.
835), but it is not significantly different from plasma pTau181 or GFAP
.

If CSF Aβ42/40 (which changes earlier than Aβ-PET) is used to assess Aβ burden, the performance of plasma pTau231 is significantly better than other biomarkers (AUC = 0.
814, P <0.
001)
.

Researchers believe that plasma pTau231 can be used to distinguish between Aβ-positive and asymptomatic people who are negative
.

Therefore, plasma pTau231 may be able to flex its muscles in patient recruitment and promote the development of AD drugs
.

In addition, research by Eisai and C2N Diagnostics also showed (LBR08) that measuring plasma Aβ42/40 with C2N PrecivityADTM can predict the pathology of brain amyloid, with AUC values ​​up to 0.
81-0.
84, and it is not affected by age and APOE4 status.

.

However, the Genentech team’s research has reminded researchers who are carrying out AD clinical research (LBR11).
Their research shows that although the plasma Aβ42/40 ratio is a good indicator, it is still not good to screen for AD.
The main problem It is the low degree of discrimination, and at this point, it is far inferior to the effect of CSF Aβ42/40
.

Perhaps there is still a long way to go before plasma Aβ42/40 can be used to screen patients in clinical trials
.

The last thing I want to introduce is the magic AD detection method (LB03) of the Italian Diadem team
.

The name of this test method is AlzoSure®Predict, and it is also a blood test method that uses antibodies to detect the conformational changes of p53 protein (abbreviation: U-p53AZ)
.

From the data point of view, the AD biomarker U-p53AZ was discovered this year
.

Judging from the data released at the conference, AlzoSure®Predict predicts that individuals with subjective memory complaints (SMC) will have an AUC of 98%, a sensitivity of 100%, and a specificity of 95%.
What's more, it can be 6 in advance.
Found in years
.

In addition, Alzosure®Predict distinguishes patients with mild cognitive impairment (MCI) from AD patients with an AUC of 97%, a sensitivity of 94%, and a specificity of 94%
.

The data really looks surprising, in any case, look forward to the release of further research results
.

Who would have thought it turned out to be p53.
Generally speaking, for the "big monster" of Alzheimer's disease, this year's Alzheimer's disease clinical trial conference did not have exciting research data, especially targeting the pathological protein Aβ And Tau's star drug
.

Perhaps, it's really time to seriously consider other ways
.

In fact, the Alzheimer's Disease Drug Discovery Foundation (ADDF) released during this year's Alzheimer's Disease Clinical Trial Conference the "Alzheimer's Disease Clinical Trial Report 2021"[2], which has already released a signal: The era of drug development focused on Aβ and Tau has passed! According to ADDF statistics, 77% of the 118 clinical trials in the treatment of Alzheimer's disease are using new targets other than Aβ and Tau
.

There is no doubt that a great era of "a hundred flowers blossom, a hundred schools of thought contend" has arrived
.

Of course, to achieve the goal of defeating Alzheimer's disease, mankind still has a long, long way to go
.

Reference: [1].
https:// Author of this articleBioTalker