Ten years of drinking ice, the blood is not cold: The new drug Gantenerumab for Alzheimer's disease is beginning to shine

*For medical professionals only

From July 31 to August 4, 2022, the annual Alzheimer's Association International Conference (AAIC-2022) was successfully held

DMT is the main concept

1

Gantenerumab's path to research and development

Mountains and rivers, willows and flowers

As mentioned earlier, Aβ monoclonal antibodies may act on aggregates of different levels of the Aβ protein, such as monomers, oligomers, fibers, and plaques; Drugs differ in affinity for these protein aggregates, which can lead to differences

The Gantenerumab Clinical Development Program has been running for more than 10 years and covers both sporadic and familial AD populations

2

Clinical scores and biomarkers improved both

Gantenerumab's new results are encouraging

The SCarlet RoAD study included a total of 700 patients in the prodromal stage of AD, divided into three groups of placebo, Gantenerumab 105 mg, and 225 mg on a 1:1:1 basis, with subcutaneous injection of the drug every four weeks, and the primary endpoint of the study was a 2-year CDR-SB score (Clinical Dementia Rating Scale - Sum of Boxes [CDR-SB], Clinical Dementia Rating Scale - Total Score, A higher score indicates poor cognitive and daily functioning).

Post-mortem analysis of two clinical trials found that the degree of amyloid reduction in patients correlated with Gantenerumab dose, and the exposure-dependent effects of amyloid reduction and cognitive decline suggested that the dose of Gantenerumab in the SCarlet RoAD study was also too low

Figure 1: Drug titration protocols
were determined in SR OLE and MR OLE studies based on the status of patients carrying apolipoprotein Eε4 carriers and previous gantenerumab dose exposure levels.

PBO: placebo control group; 105: 105 mg subcutaneous injection group; 225: 225 mg subcutaneous injection group; SR, SCarlet RoAD ，MR, Marguerite RoAD

Participants who completed SCarlet RoAD OLE and Marguerite RoAD OLE studies and met the criteria were included in the rolling study Open RoAD, with the following criteria: participants who participated in either parent study and received 1,200 mg of Gantenerumab for up to 5 years and continued to receive the same dose of Gantenerumab for 2 years
.

The main objectives of Open RoAD are to assess the long-term safety and tolerability of subcutaneous Gantenerumab, long-term clinical efficacy and the long-term effect
of Gantenerumab on MRI measurements and plasma biomarkers.

At this AAIC meeting, the results of Open RoAD were published, and data from the OR study showed that the long-term therapeutic dose of 1200 mg Gantenerumab SC Q4W was well tolerated, there were no new or unexpected safety findings, and long-term safety studies on Gantenerumab could be continued; The effect of long-term use of Gantenerumab on disease progression needs to be explored
.

SCarlet RoAD OLE and Marguerite RoAD OLE lack placebo control and have limitations
in providing reliable evidence of gantenerumab effectiveness.

To further explain the results of both studies, the researchers joined an external control group
from the ADNI (the Alzheimer's Disease Neuroimaging Initiative Cohort) cohort.

According to the enrollment criteria, 77 participants were finally included in the SCarlet RoAD OLE, 87 participants in the Marguerite RoAD OLE, and 430 participants in the ADNI, and the control group matched the baseline characteristics of the subjects in OLE (Figure 2).

Figure 2.
SR and MR OLE subjects had consistent
baseline characteristics with the matched ADNI control group.

ADAS-Cog13, Alzheimer's Disease Assessment Scale- Cognitive Subscale 13 entries; BMI, Body Mass Index; CDR-SB, Total score of the Clinical Dementia Assessment Scale; MR, Marguerite RoAD; MMSE, Simple Intelligent Mental Status Check; OLE, Open Label Research; SR, SCarlet RoAD

CDR-SB was the primary cognitive endpoint in early clinical studies
of AD.

The analysis showed that the absolute value of the CDR-SB change in the treatment group was -0.
753 (95% CI: -1.
468, -0.
039) after 104 weeks of treatment compared with the control group, and the proportion was -23.
9%; After 156 weeks of treatment, the absolute value of the CDR change in the treatment group was -1.
844 (95% CI: -2.
882, -0.
806), with a ratio of -38.
9% (Figure 3).


Previous studies have shown that for mild cognitive impairment (MCI) and mild AD, CDR-SB 0.
98 and 1.
63 represent clinically significant cognitive changes
, respectively.

In this study, the absolute difference between the two groups of CDR-SBs in the Gantenerumab treatment group reached 1.
844 at 156 weeks compared with the reference cohort, suggesting that this improvement may have significant clinical significance
.

Figure 3.
Changes in CDR-SB scores in the Gantenerumab treatment group and control group

In addition, the ADAS-Cog13 score was -35.
1% after 2 years compared with the control group and -35.
6% after 3 years (Figure 4); MMSE scores were +16.
8% after 2 years compared to +18.
8% after 3 years (Figure 4).


All of the above results suggest that continued Gantenerumab treatment reduces amyloidosis and alters downstream biomarkers, and that Gantenerumab treatment for 3 years may slow the trend
of CDR-SB and other indicators.

Figure 4.
Changes in ADAS-Cog13 and MMSE scores in the Gantenerumab treatment and control groups

In addition, pharmacodynamic exploration of SCarlet RoAD OLE and Marguerite RoAD OLE studies showed that after 4 weeks of treatment with Gantenerumab 1200 mg, patients had elevated plasma Aβ42 and Aβ40 levels (Figure 5
).

These effects may come directly from Gantenerumab-induced clearance of amyloid plaques in the brain, or indirectly from the prolonged stay of Aβ42 in the periphery
.

Long-term Gantenerumab treatment continues to reduce plasma pTau levels, which may come from Gantenerumab's clearance of amyloid plaques, or downstream effects on tau (Figure 5
).

Figure 5.
Changes in plasma biomarkers in patients after gantenerumab treatment

3

20 years of deep cultivation in the field

The future of Gantenerumab is promising

In the face of these surprising results of Gantenerumab, experts in the field of Alzheimer's disease in China have also expressed their expectations
.

Professor Chen Xiaochun of Union Hospital affiliated to Fujian Medical University believes that nearly two decades of profound experience and continuous attention to patient needs have provided a basis
for the development of gantenerumab under the skin.

It was developed taking into account the different needs of AD patients and their caregivers, providing greater flexibility in the way in which subcutaneous and autoinjectors are administered; The development project incorporated the experience of more than 2,600 patients and had safety data to support their ongoing assessment
.

The follow-up critical Phase III GRADUATE I and II studies, designed to provide comprehensive evidence of the risk profile of subcutaneous Gantenerumab in early AD, are expected to be published in the fourth quarter of 2022 and are expected to be published
.

In addition, collaborations with the Alzheimer's disease community are conducting or planning more research on Gantenerumab to better meet the prevention needs of current and future Alzheimer's patients, as well as other populations
.

Professor Yu Jintai of the Department of Neurology of Huashan Hospital affiliated to Fudan University believes that the monoclonal antibody gantenerumab specifically acts on Aβ, and the clinical trial research of the drug has been more than 20 years, and has accumulated rich experience
in its development.

At the AAIC conference, the results of the efficacy analysis after the matching of SCarlet RoAD (SR) and Marguerite RoAD (MR) OLE were presented, and the design of THE SKYLINE related gantenerumab-related secondary prevention study was announced, which was based on the pre-screening of blood biomarkers and the determination of inclusion criteria for amyloid PET and CSF.
Will accelerate the pace
of Gantenerumab's future clinical research.

For more information on the two professors' testimonials, please click here: