– Focus on CDR-SB score changes
– Can these score changes be felt clinically?
Provided by: Biogen homepage capture
In 1906, Alois Alzheimer reported the first patient with Alzheimer’s disease, marking the beginning of our understanding of this devastating condition. Over the years, several drugs have been developed to alleviate the clinical symptoms associated with Alzheimer’s disease, such as donepezil, rivastigmine, galantamine, and memantine. However, none of these drugs addressed the underlying causes of the disease – amyloid plaques and abnormal tau proteins. The search for a treatment that could fundamentally cure Alzheimer’s disease has been a series of disappointments, but the hope remained.
Finally, on June 7, 2021, the US FDA conditionally approved aducanubmab (trade name: Aduhelm), developed by Eisai and Biogen, as the first radical anti-amyloid treatment. This was a significant milestone in the fight against Alzheimer’s disease. Subsequently, other drugs like recanemab and donanemab have also received approval or are in the process of seeking approval for their efficacy in treating Alzheimer’s disease.
Aducanumab, recanemab, and donanemab are all classified as amyloid-removing monoclonal antibodies, but they differ in their mechanism of action. While aducanumab binds to aggregated forms of amyloid, recanemab selectively binds to soluble amyloid protofibrils, and donanemab targets aggregated beta-amyloid in the form of pyroglutamate found in amyloid plaques.
These drugs underwent phase 3 clinical trials that evaluated their effectiveness in patients with mild Alzheimer’s disease. The primary measure of efficacy was the change in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, which is a commonly used tool to assess the severity of dementia. The CDR-SB score assesses various areas such as memory, judgment, social activity, and hygiene.
In the phase 3 clinical trials, aducanumab, recanemab, and donanemab showed positive effects in reducing the progression of Alzheimer’s disease. The CDR-SB scores increased by 1.35, 1.21, and 1.72 points in the treatment groups compared to the control groups, implying less deterioration in the treated patients. These score changes, although seemingly small, are significant in the context of Alzheimer’s disease progression.
It is important to note that the natural course of Alzheimer’s disease leads to an increase in the CDR-SB score each year as the disease advances. Therefore, any treatment that slows down this progression by approximately 25% can be considered as having a substantial therapeutic effect. However, it is crucial to consider the cost and efficiency aspects of these treatments, as they can be expensive and require additional medical procedures.
Additionally, the phase 3 clinical trials focused on patients in the early stages of Alzheimer’s disease, and the evidence for administering these drugs to patients with moderate or severe Alzheimer’s disease is limited. Further research is needed to determine the efficacy of these drugs in a broader range of patients.
In conclusion, the development of aducanumab, recanemab, and donanemab marks significant progress in the search for a cure for Alzheimer’s disease. While these drugs have shown promising results in reducing the progression of the disease, further studies and considerations are necessary to ensure their widespread effectiveness and accessibility. The quest to find a definitive cure for Alzheimer’s disease continues, offering hope to the millions affected by this debilitating condition.
– Focus on CDR-SB score changes
– Is it a change that can be felt clinically?
Provided by: Biogen homepage capture
In 1906, 117 years ago, Alois Alzheimer reported the first Alzheimer’s patient. It was followed by donepezil (1996), rivastigmine (1997), galantamine (2000), and memantine (2003), but no Alzheimer’s treatment was found for 18 years after memantine.
Drugs focused on donepezil only improve some of the clinical symptoms of Alzheimer’s disease but do not eliminate amyloid and abnormal tau, which are known to cause Alzheimer’s disease, so they are not primary treatments for Alzheimer’s disease in a strict sense .
Since John Hardy and Gerald Higgins proposed the amyloid cascade hypothesis in 1992, research has been carried out to develop a treatment that can fundamentally cure Alzheimer’s disease by removing amyloid and plaques. was a series of frustrations. Still, the hope of being able to fundamentally cure Alzheimer’s disease has not disappeared.
Finally, on June 7, 2021, the US FDA conditionally approved the use of aducanubmab (trade name: Aduhelm), co-developed by Eisai and Biogen, as the first radical anti-amyloid treatment.
Following aducanumab, the US FDA granted accelerated approval to Eisai and Biogen (brand name Leqembi) in January 2023 and formal approval in June. In addition, Japan’s Ministry of Health and Welfare also approved the use of recanemab on the 21st, and in Korea, an application for permission for recanemab was submitted to the Ministry of Food and Drug Safety in June.
In addition, Eli Lilly announced the final clinical results of donanemab at the Alzheimer’s Association International Conference (AAIC) 2023 in July, and based on these results, it has applied for approval to the US FDA.
Aducanumab, recanemab, and donanemab are classified as amyloid-removing monoclonal antibodies, but show differences in their mechanism of action. Aducanumab does not bind to amyloid monomers, but binds to aggregated forms of amyloid. Recanemab binds selectively to soluble amyloid protofibrils. Donanemab binds to beta-amyloid in the form of pyroglutamate, which is aggregated in amyloid plaques.
A phase 3 clinical trial using the above antibody was conducted for 18 months in patients with mild Alzheimer’s disease (mild cognitive impairment and mild-stage Alzheimer’s dementia) with a Clinical Dementia Score CDR of 0.5 and 1, and demonstrated clinical Dementia Sum Score efficacy. of Boxes (CDR-SB) as a variable for evaluation.
For reference, the CDR is most commonly used to evaluate the severity of dementia in clinical practice. Scores are calculated by evaluating six areas: ‘memory’, ‘community’, ‘judgement and problem solving’, ‘social activity’, ‘family life and hobbies’, and ‘hygiene and grooming’. The final score is the total CDR (Global CDR, 0, 0.5, 1, 2, 3 points). The higher the score, the more severe the level of dementia.
The following is a summary of CDR-SB score changes in phase 3 clinical trials of aducanumab, recanemab, and donanemab.
In the EMERGE study, which showed statistical significance among the two phase 3 clinical trials (EMERGE Trial and ENGAGE Trial), aducanumab increased CDR-SB in the control group by 1.74 points over 18 months, while the high-dose treatment group increased by 1.35 points, from compared to the control group In the treatment group, 0.39 points (23%) showed less deterioration.
In addition, recanemab CDR-SB increased by 1.66 points in the control group in the 18-month phase 3 clinical trial (HR Clarity Trial), but increased by 1.21 points in the treatment group, which was less than 0.45 points (27%) in the treatment group compared to the control group It got worse.
Meanwhile, in the phase 3 clinical trial (Trailblazer-Alz 2 Trial) conducted during the same period, donanemab worsened CDR-SB in the control group by 2.42 points, but in the treatment group, it declined by 1.72 points, reducing progression dementia 0.7 points (29%) compared to the control group, announced that it was delayed.
If the above treatments slow down the progression of Alzheimer’s disease by around 25%, it is felt that the therapeutic effect of the drugs is very great. However, what should be noted here is that the total CDR-SB score is 18 points and there is a natural increase in the CDR-SB score each year as the disease progresses.
The CDR-SB score increases gradually as Alzheimer’s disease progresses When the total CDR is 0.5 points, the CDR-SB increases by 1.43 points each year, and when the total CDR is 1 point, the score increases by 1.9 points each year. Annual changes in these CDR-SB scores are usefully used to evaluate the effectiveness of treatments in Alzheimer’s clinical trials.
Given that most of the phase 3 clinical trials that have been conducted so far are conducted on patients with early Alzheimer’s disease (CDR 0.5 and CDR 1). In this subject, the CDR-SB increases by approximately 1.67 points per year, and given that a typical clinical trial period is 18 months, an increase of 2.5 points can be expected during this period. Among the three drugs above, the control group in the clinical trial of donanemab showed the most similar score change (2.42 points). On the other hand, unlike the donanemab control group, the control group in the study of aducanumab and recanemab had a smaller increase in CDR-SB score than expected.
The three treatments above showed a difference of about 0.5 points in the CDR-SB score change between the control group and the treatment group over 18 months. It seems necessary. This is because in actual clinical practice, especially in the early stages of Alzheimer’s disease, it is difficult to feel changes in the global CDR, which is evaluated with a whole 3-point system.
In addition, the cost and efficiency aspects cannot be considered. Aduhelm and Rekembi drug costs alone exceed 30 million won per year. Before drug administration, brain MRI was performed from time to time to check for drug side effects such as brain edema (ARIA-E) and brain hemorrhage (ARIA-H) and amyloid PET imaging cost more than 1 million and was won for a diagnosis of Alzheimer’s disease. ■ The reason for this is that the additional cost incurred during filming is also not insignificant.
In addition, phase 3 clinical trials of the above treatments were carried out on patients in the early stages of Alzheimer’s disease (mild cognitive impairment and mild stage Alzheimer’s dementia). As there is insufficient evidence for administration in patients with moderate or severe Alzheimer’s disease, there is still a limitation that it cannot be given to all patients with Alzheimer’s disease.
reference material
Alzheimer’s. Hyeon-deok Yang, Min-ho Moon and Young-min Park. Dementia Books. 2020
[칼럼] Assessment of Clinical Dementia Score (CDR)
[칼럼] Development of aducanumab, US FDA approval, and subsequent controversy
Budd Haeberlein S, Aisen PS, Barkhof F, et al. Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease. J Prev Alzheimers Dis. 2022; 9(2): 197-210. doi:10.14283/jpad.2022.30
van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer’s Disease. N Engl J Med. 2023; 388(1):9-21. doi: 10.1056/NEJMoa2212948
Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992 Apr 10; 256(5054): 184-5. doi: 10.1126/science.1566067.
Williams MM, Storandt M, Roe CM, Morris JC. Progression of Alzheimer’s disease as measured by Clinical Dementia Score Sum of the Boxes scores. Alzheimer’s dementia. 2013; 9(1 Suppl):S39-S44. doi: 10.1016/j.jalz.2012.01.005
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