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▎The content team editor of WuXi AppTec last weekend, Eli Lilly and Company (Eli Lilly and Company) published in the "New England Journal of Medicine" the detailed results of its Phase 2 clinical trial of its Alzheimer's disease (AD) antibody therapy donanemab.
This result has received widespread attention from the industry, because in the history of AD drug development, multiple research therapies have been "smashed into the sand" in late-stage clinical trials.
However, last year, the anti-β-amyloid antibody therapy aducanumab jointly developed by Biogen and Eisai achieved a breakthrough in phase 3 clinical trials.
It is currently undergoing review by the US FDA.
May get a response this summer.
Donanemab is also a monoclonal antibody therapy targeting β-amyloid protein and has many similarities with aducanumab in the mechanism of action.
As one of the most important hypotheses for AD disease, the "amyloid" hypothesis has also received many suspicions due to the frustration of targeted therapies in clinical trials in recent years.
Following aducanumab, the positive clinical results of donanemab are expected to further stimulate the development of targeted amyloid-based therapies.
This year, WuXi AppTec's content team will give readers a detailed interpretation of donanemab's clinical trial results and the enlightenment these results will bring to the development of AD therapies.
Donanemab reaches the primary endpoint of the Phase 2 clinical trial.
In this Phase 2 clinical trial, a total of 257 early-stage AD patients were randomized to receive either donanemab or placebo treatment.The researchers used an evaluation index called the integrated Alzheimer's Disease Rating Scale (iADRS) to comprehensively evaluate the cognitive ability and ability of daily living of patients.
After 76 weeks of treatment, the score results showed that the reduction in iADRS scores of patients treated with donanemab was 32% less than that of the placebo group (p=0.
04), reaching the primary endpoint of the trial.
This means that the decline in cognitive and daily living abilities of patients receiving donanemab treatment has been alleviated.
▲The reduction rate of iADRS score in AD patients treated with donanemab was slower than that in the placebo group (picture source: reference [1]) At the same time, positron scanning (PET) imaging showed that donanemab can quickly clear the amyloid deposits in the brain of patients.
After 6 months of treatment, 40% of patients had a negative PET test, meaning that the level of amyloid deposits in their brains was not significantly different from that of healthy people.
After 18 months of treatment, 68% of patients reached a level of negative PET testing.
▲Donanemab significantly clears the amyloid deposits in the brains of patients (picture source: reference [1]) In addition, donanemab also exhibits delayed cognitive ability and delayed cognitive ability in multiple secondary endpoints for detecting cognitive ability and ability of daily living The same trend of decline in the ability of daily living.
Previously, a variety of research therapies targeting amyloid protein did not perform well in clinical trials.
So what enlightenment can the success of donanemab in Phase 2 clinical trials bring us? Is drastically reducing amyloid deposits in the brain the key to alleviating symptoms? The "amyloid hypothesis" pointed out that the cause of AD is that the amyloid precursor (APP) in the patient’s brain is cleaved to produce amyloid (Aβ), and these Aβ monomers will continue to aggregate to form dimers.
, Oligomers, eventually form amyloid deposits. Although there are currently a variety of research therapies targeting amyloid, their mechanisms of action are different: for example, inhibitors targeting BACE are designed to reduce the cleavage of APP to generate Aβ monomers, and they may have a role in reducing Aβ monomers.
Better results, but it may not be able to effectively remove the amyloid deposits that have formed.
Although antibody therapy targeting soluble amyloid protein can help to remove them from the blood and brain by binding to amyloid protein, within the therapeutic dose range, monoclonal antibodies that can bind to Aβ monomer can interact with amyloid.
Before protein deposition is combined, it has been combined with Aβ monomers and oligomers in blood and cerebrospinal fluid, causing them to no longer be combined with amyloid deposition.
▲Donanemab is designed to specifically combine with the amyloid deposits in the brain to promote their removal (the position of the red box standard, picture source: reference [3]) Donanemab and the amyloid deposits in the brain Specific Aβ subtypes bind, which can skip the obstacles of Aβ monomers in the blood, and specifically bind to amyloid deposits in the brain to accelerate their clearance.
This mechanism of action is very similar to that of Bojian's aducanumab.
Moreover, the results of Biogen's phase 3 clinical trial also showed that in patients who can continue to receive high doses of aducanumab, PET testing found that their brain amyloid levels decreased even more, and the cognitive ability of these patients decreased speed Also got a more significant delay.
These results may mean that research-in-progress therapies that target amyloid have not worked well before, possibly because they have not been able to reduce amyloid deposits in the brain to a sufficiently low level.
Based on this concept, Roche has launched two phase 3 clinical trials to test the effect of high-dose amyloid antibody gantenerumab in early AD patients.
This monoclonal antibody tends to bind to the Aβ protein accumulated in the brain and degrade amyloid deposits by recruiting microglia and activated macrophages.
The company has also developed a "brain shuttle" technology that can help gantenerumab cross the blood-brain barrier, thereby more effectively removing amyloid deposits in the brain.
Using the right treatment for the right patient at the right time AD is a disease that lasts for decades.
Amyloid deposits have appeared in the brain of the patient more than 10 years before the patient has clinical symptoms of cognitive decline.
The AD patient group is a very heterogeneous group, and each patient's disease progression speed, disease development stage, and reasons that affect disease development are different.
Therefore, it is also conceivable that therapies that target amyloid deposition will only have a curative effect on some patients.
Image source: 123RF At this year's WuXi AppTec Global Forum, Professor Rudolph Tanzi of Harvard Medical School pointed out that the treatment of AD requires "appropriate therapy for the right patient at the right time.
"
When amyloid deposits appear in the early stage of the disease, the treatment of removing deposits may be effective.
However, after neuroinflammation has occurred in the brain, simply removing amyloid deposits may not be effective because of neuroinflammation in the brain at this time.
Death may be more serious than amyloid deposition.
Related Reading: Fighting Aging and Nervous System Diseases: Just a Hit? | WuXi AppTec Global Forum Records This is like when treating COVID-19, using antiviral therapy or neutralizing antibody therapy after the initial infection with the new coronavirus can achieve good results, but once the patient's condition is so severe that he has been hospitalized, it inhibits the body Excessive inflammation has become a top priority to save lives.
At this time, simply eliminating the virus will not have a good therapeutic effect.
The common feature of clinical trials of Donanemab and aducanumab is the use of biomarkers to screen the patient population for treatment.
In clinical trials of aducanumab, researchers used PET to detect the degree of amyloid deposition to screen patients for treatment.
In the clinical trial of donanemab, the researchers not only used PET to detect amyloid deposits, but also used similar techniques to detect the level of tau protein in the patient's brain.
Tau protein, like amyloid deposits, is a hallmark feature in the patient's brain.
Its appearance is generally later than amyloid deposits, and is more closely related to the decline in patients' cognitive levels.
In the clinical trial of donanemab, researchers did not select patients with too high tau protein levels, because these patients may have entered a more advanced stage of disease.
At this time, simply reducing amyloid levels may not be effective.
Picture source: 123RF Previously, Dr.
David Elmaleh, CEO of AZTherapies, also mentioned in an interview that the failure of multiple clinical trials for the treatment of AD did not mean that the scientific theory behind drug development was wrong, but that the disease There are problems in the description of progress, the design of clinical trials, and patient heterogeneity.
Related reading: Alzheimer’s disease research and development have failed repeatedly, he said it’s not a drug problem | Interview At this year’s WuXi AppTec Global Forum, Dr.
Howard Fillit, Chief Scientific Officer of the Alzheimer’s Disease Drug Discovery Foundation also pointed out that in clinical practice In the design of the trial, the field of Alzheimer's disease is decades behind the field of cancer.
However, in 2020, “we can finally say that we know how to really conduct clinical trials, and we will get better and better in
the future .
” Facing the future: “multi-pronged approach” brings hope to Eli Lilly’s donanemab phase 2 clinical trial The results still need to be verified in larger clinical trials.
Due to the complexity of AD disease, even if therapies targeting amyloid are successful, they are unlikely to have an effect on all types of patients.
Therefore, only by targeting the different stages of AD disease and using a variety of innovative treatment modes, can AD patients be treated more effectively and comprehensively.
Fortunately, the previous innovative therapies targeting inflammation have also obtained positive results in phase 2b/3 clinical trials for the treatment of Alzheimer's disease.
Recently, Cognito Therapeutics, a company co-founded by Professor Lihui Cai of the Massachusetts Institute of Technology, announced that its innovative digital therapy for the treatment of AD through acousto-optic stimulation will not only delay the decline of patients’ memory and cognitive abilities in phase 2 clinical trials, but also improve the brain The rate of shrinkage has also been reduced by 61%.
Image source: 123RF At the WuXi AppTec Global Forum in January this year, experts also mentioned that innovative treatment models such as gene therapy and antisense oligonucleotide therapy may bring hope to the treatment of AD.
Dr.
Irene Griswold-Prenner, CEO and Chief Scientific Officer of Nitrome Biosciences, said that although there is still a long way to go to achieve the goal, the inflection point of drug development in the field of neurodegenerative diseases is coming! Note: This article is intended to introduce medical and health research, not to recommend treatment options.
If you need guidance on treatment plans, please go to a regular hospital for treatment.
Reference: [1] Mintun et al.
, (2021).
Donanemab in Early Alzheimer's Disease.
NEJM, DOI: 10.
1056/NEJMoa2100708[2] Lilly's donanemab slowed Alzheimer's disease progression in Phase 2 trial: full data presented at AD/PD™ 2021 and published in NEJM.
Retrieved March 13, 2021, from https://investor.
lilly.
com/news-releases/news-release-details/lillys-donanemab-slowed-alzheimers-disease-progression-phase-2[3 ] Therapeutic development for Alzheimer's disease at Eli Lilly and Company.
Retrieved January 11, 2021, from https://media.
nature.
com/full/nature-cms/uploads/ckeditor/attachments/8368/Lilly.
pdf.
This result has received widespread attention from the industry, because in the history of AD drug development, multiple research therapies have been "smashed into the sand" in late-stage clinical trials.
However, last year, the anti-β-amyloid antibody therapy aducanumab jointly developed by Biogen and Eisai achieved a breakthrough in phase 3 clinical trials.
It is currently undergoing review by the US FDA.
May get a response this summer.
Donanemab is also a monoclonal antibody therapy targeting β-amyloid protein and has many similarities with aducanumab in the mechanism of action.
As one of the most important hypotheses for AD disease, the "amyloid" hypothesis has also received many suspicions due to the frustration of targeted therapies in clinical trials in recent years.
Following aducanumab, the positive clinical results of donanemab are expected to further stimulate the development of targeted amyloid-based therapies.
This year, WuXi AppTec's content team will give readers a detailed interpretation of donanemab's clinical trial results and the enlightenment these results will bring to the development of AD therapies.
Donanemab reaches the primary endpoint of the Phase 2 clinical trial.
In this Phase 2 clinical trial, a total of 257 early-stage AD patients were randomized to receive either donanemab or placebo treatment.The researchers used an evaluation index called the integrated Alzheimer's Disease Rating Scale (iADRS) to comprehensively evaluate the cognitive ability and ability of daily living of patients.
After 76 weeks of treatment, the score results showed that the reduction in iADRS scores of patients treated with donanemab was 32% less than that of the placebo group (p=0.
04), reaching the primary endpoint of the trial.
This means that the decline in cognitive and daily living abilities of patients receiving donanemab treatment has been alleviated.
▲The reduction rate of iADRS score in AD patients treated with donanemab was slower than that in the placebo group (picture source: reference [1]) At the same time, positron scanning (PET) imaging showed that donanemab can quickly clear the amyloid deposits in the brain of patients.
After 6 months of treatment, 40% of patients had a negative PET test, meaning that the level of amyloid deposits in their brains was not significantly different from that of healthy people.
After 18 months of treatment, 68% of patients reached a level of negative PET testing.
▲Donanemab significantly clears the amyloid deposits in the brains of patients (picture source: reference [1]) In addition, donanemab also exhibits delayed cognitive ability and delayed cognitive ability in multiple secondary endpoints for detecting cognitive ability and ability of daily living The same trend of decline in the ability of daily living.
Previously, a variety of research therapies targeting amyloid protein did not perform well in clinical trials.
So what enlightenment can the success of donanemab in Phase 2 clinical trials bring us? Is drastically reducing amyloid deposits in the brain the key to alleviating symptoms? The "amyloid hypothesis" pointed out that the cause of AD is that the amyloid precursor (APP) in the patient’s brain is cleaved to produce amyloid (Aβ), and these Aβ monomers will continue to aggregate to form dimers.
, Oligomers, eventually form amyloid deposits. Although there are currently a variety of research therapies targeting amyloid, their mechanisms of action are different: for example, inhibitors targeting BACE are designed to reduce the cleavage of APP to generate Aβ monomers, and they may have a role in reducing Aβ monomers.
Better results, but it may not be able to effectively remove the amyloid deposits that have formed.
Although antibody therapy targeting soluble amyloid protein can help to remove them from the blood and brain by binding to amyloid protein, within the therapeutic dose range, monoclonal antibodies that can bind to Aβ monomer can interact with amyloid.
Before protein deposition is combined, it has been combined with Aβ monomers and oligomers in blood and cerebrospinal fluid, causing them to no longer be combined with amyloid deposition.
▲Donanemab is designed to specifically combine with the amyloid deposits in the brain to promote their removal (the position of the red box standard, picture source: reference [3]) Donanemab and the amyloid deposits in the brain Specific Aβ subtypes bind, which can skip the obstacles of Aβ monomers in the blood, and specifically bind to amyloid deposits in the brain to accelerate their clearance.
This mechanism of action is very similar to that of Bojian's aducanumab.
Moreover, the results of Biogen's phase 3 clinical trial also showed that in patients who can continue to receive high doses of aducanumab, PET testing found that their brain amyloid levels decreased even more, and the cognitive ability of these patients decreased speed Also got a more significant delay.
These results may mean that research-in-progress therapies that target amyloid have not worked well before, possibly because they have not been able to reduce amyloid deposits in the brain to a sufficiently low level.
Based on this concept, Roche has launched two phase 3 clinical trials to test the effect of high-dose amyloid antibody gantenerumab in early AD patients.
This monoclonal antibody tends to bind to the Aβ protein accumulated in the brain and degrade amyloid deposits by recruiting microglia and activated macrophages.
The company has also developed a "brain shuttle" technology that can help gantenerumab cross the blood-brain barrier, thereby more effectively removing amyloid deposits in the brain.
Using the right treatment for the right patient at the right time AD is a disease that lasts for decades.
Amyloid deposits have appeared in the brain of the patient more than 10 years before the patient has clinical symptoms of cognitive decline.
The AD patient group is a very heterogeneous group, and each patient's disease progression speed, disease development stage, and reasons that affect disease development are different.
Therefore, it is also conceivable that therapies that target amyloid deposition will only have a curative effect on some patients.
Image source: 123RF At this year's WuXi AppTec Global Forum, Professor Rudolph Tanzi of Harvard Medical School pointed out that the treatment of AD requires "appropriate therapy for the right patient at the right time.
"
When amyloid deposits appear in the early stage of the disease, the treatment of removing deposits may be effective.
However, after neuroinflammation has occurred in the brain, simply removing amyloid deposits may not be effective because of neuroinflammation in the brain at this time.
Death may be more serious than amyloid deposition.
Related Reading: Fighting Aging and Nervous System Diseases: Just a Hit? | WuXi AppTec Global Forum Records This is like when treating COVID-19, using antiviral therapy or neutralizing antibody therapy after the initial infection with the new coronavirus can achieve good results, but once the patient's condition is so severe that he has been hospitalized, it inhibits the body Excessive inflammation has become a top priority to save lives.
At this time, simply eliminating the virus will not have a good therapeutic effect.
The common feature of clinical trials of Donanemab and aducanumab is the use of biomarkers to screen the patient population for treatment.
In clinical trials of aducanumab, researchers used PET to detect the degree of amyloid deposition to screen patients for treatment.
In the clinical trial of donanemab, the researchers not only used PET to detect amyloid deposits, but also used similar techniques to detect the level of tau protein in the patient's brain.
Tau protein, like amyloid deposits, is a hallmark feature in the patient's brain.
Its appearance is generally later than amyloid deposits, and is more closely related to the decline in patients' cognitive levels.
In the clinical trial of donanemab, researchers did not select patients with too high tau protein levels, because these patients may have entered a more advanced stage of disease.
At this time, simply reducing amyloid levels may not be effective.
Picture source: 123RF Previously, Dr.
David Elmaleh, CEO of AZTherapies, also mentioned in an interview that the failure of multiple clinical trials for the treatment of AD did not mean that the scientific theory behind drug development was wrong, but that the disease There are problems in the description of progress, the design of clinical trials, and patient heterogeneity.
Related reading: Alzheimer’s disease research and development have failed repeatedly, he said it’s not a drug problem | Interview At this year’s WuXi AppTec Global Forum, Dr.
Howard Fillit, Chief Scientific Officer of the Alzheimer’s Disease Drug Discovery Foundation also pointed out that in clinical practice In the design of the trial, the field of Alzheimer's disease is decades behind the field of cancer.
However, in 2020, “we can finally say that we know how to really conduct clinical trials, and we will get better and better in
the future .
” Facing the future: “multi-pronged approach” brings hope to Eli Lilly’s donanemab phase 2 clinical trial The results still need to be verified in larger clinical trials.
Due to the complexity of AD disease, even if therapies targeting amyloid are successful, they are unlikely to have an effect on all types of patients.
Therefore, only by targeting the different stages of AD disease and using a variety of innovative treatment modes, can AD patients be treated more effectively and comprehensively.
Fortunately, the previous innovative therapies targeting inflammation have also obtained positive results in phase 2b/3 clinical trials for the treatment of Alzheimer's disease.
Recently, Cognito Therapeutics, a company co-founded by Professor Lihui Cai of the Massachusetts Institute of Technology, announced that its innovative digital therapy for the treatment of AD through acousto-optic stimulation will not only delay the decline of patients’ memory and cognitive abilities in phase 2 clinical trials, but also improve the brain The rate of shrinkage has also been reduced by 61%.
Image source: 123RF At the WuXi AppTec Global Forum in January this year, experts also mentioned that innovative treatment models such as gene therapy and antisense oligonucleotide therapy may bring hope to the treatment of AD.
Dr.
Irene Griswold-Prenner, CEO and Chief Scientific Officer of Nitrome Biosciences, said that although there is still a long way to go to achieve the goal, the inflection point of drug development in the field of neurodegenerative diseases is coming! Note: This article is intended to introduce medical and health research, not to recommend treatment options.
If you need guidance on treatment plans, please go to a regular hospital for treatment.
Reference: [1] Mintun et al.
, (2021).
Donanemab in Early Alzheimer's Disease.
NEJM, DOI: 10.
1056/NEJMoa2100708[2] Lilly's donanemab slowed Alzheimer's disease progression in Phase 2 trial: full data presented at AD/PD™ 2021 and published in NEJM.
Retrieved March 13, 2021, from https://investor.
lilly.
com/news-releases/news-release-details/lillys-donanemab-slowed-alzheimers-disease-progression-phase-2[3 ] Therapeutic development for Alzheimer's disease at Eli Lilly and Company.
Retrieved January 11, 2021, from https://media.
nature.
com/full/nature-cms/uploads/ckeditor/attachments/8368/Lilly.
pdf.
