-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
-
Cosmetic Ingredient
- Water Treatment Chemical
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
*For medical professionals only
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease and has the fastest growing number of patients, with PD affecting about 1% of people over 60 years of age in
high-income countries.
PD is characterized by loss of dopaminergic neurons in the substantia nigra compact, aggregation of α synuclein (α-syn) to form Lewy Body (LBS) and Lewy nerve fibers (Lewy Necrites).
。 Due to the loss of dopaminergic neurons in patients, exogenous dopamine supplementation can significantly improve symptoms, but disease progression cannot be delayed and most patients develop drug
resistance after long-term use.
Therefore, scientists have shifted their research focus to α-syn, working on the development of anti-PD drugs
that target α-syn.
In early August, the New England Journal of Medicine published back-to-back the results
of two clinical trials targeting α-synuclein monoclonal antibody for the drug treatment of early PD.
The two drugs and their counterparts are Prasinezumab and PASADENA and Cinpanemab and SPARK, two highly anticipated α-syn monoclonal antibodies bibifold: After 52 weeks of use, patients in the two experimental groups of patients with movement disorders learned the Unified Parkinson's Disease Rating Scale (MDS-UPDRS).
There was no significant change in scores from baseline compared to the respective controls, and monoclonal antibody therapy did not significantly delay the death
of dopaminergic neurons when single-photon emission computed tomography (SPECT) assessed dopamine transporter levels in the hemispherical putamen.
Figure 1: Prasinezumab and the PASADENA study and the Cinpanemab and SPARK studies were published simultaneously in the New England Journal of Medicine in early August
Speaking of failure, this is not the first time Prasinezumab has
faced failure.
As early as 2020, the primary endpoint of alleviating the progression of motor and non-motor symptoms of PD was not met in clinical trials with Prasinezumab as intervention, but there was relief
on exploratory measures and secondary endpoints.
This also provides a premise
for the confirmation of the main endpoint of this study.
A total of 316 participants with early PD were included in this clinical study, which were randomly divided into placebo group, 1500mg/4 weeks Prasinezumab intravenous group and 4500mg/4 weeks Prasinezumab intravenous group
according to 1:1:1.
The primary endpoint was the change in MDS-UPDRS score from baseline at week 52 of medication (higher scores lead to more severe symptoms), and the secondary endpoint was dopamine transporter levels in the hemispherical putamen, which was confirmed
by 123I-iodoflurane SPECT imaging.
At baseline, the mean MDS-UPDRS scores in the placebo group, the 1500 mg group and the 4500 mg group were 32.
0, 31.
5 and 30.
8, respectively, and the increase in the mean MDS-UPDRS score in the three groups after 52 weeks was 9.
4± 1.
2, 7.
4±1.
2 (difference compared with placebo, –2.
0; 80% CI, –4.
2~0.
2; P= 0.
24) and 8.
8±1.
2 (difference compared with placebo, –0.
6; 80% CI, –2.
8~1.
6; P = 0.
72), and spect images also did not differ
significantly between the three groups.
While efficacy was not proven, 19% and 34% of participants in the 1500 mg and 4500 mg groups experienced infusion reactions (compared to 16.
2% in the placebo group) and serious adverse events occurred in 6.
7% and 7.
5% of participants in both groups, respectively (This figure was 4.
8% in the placebo group).
Like Prasinezumab, the failure of Cinpanemab is not news
.
Information that Cinpanemab did not meet the primary and secondary endpoints in the Phase 2 clinical study SPARK was disclosed
as early as February 2021.
SPARK is a 52-week, multicenter, double-blind, phase 2 trial in which 357 participants with early PD are randomly assigned to placebo (control) or Cinpanemab (at a dose of 250 mg, 1250 mg, or 3500 mg every 4 weeks) in a 2:1:2:2 ratio.
Intravenous infusion, followed by blinded expansion of
the active therapeutic dose for up to 112 weeks.
The primary endpoints of this study were the level of change in MDS-UPDRS scores compared to baseline at weeks 52 and 72, and secondary endpoints included MDS-UPDRS scores at week 96, dopamine transporter single-photon emission computed tomography (DaT-SPECT), intraserum Cinpanemab pharmacokinetics
, and adverse events.
At week 52, the total MDS-UPDRS score in the control, 250 mg, 1250 mg, and 3500 mg groups increased by 10.
8 points and 10.
5 points from baseline, respectively (difference compared with placebo, -0.
3 points; 95% CI, -4.
9~4.
3; P=0.
90), 11.
3 points (difference compared with placebo, 0.
5 points; 95% CI, -3.
3~4.
3; P=0.
80), 10.
9 points (difference compared with placebo, 0.
1 points; 95%CI，-3.
8~4.
0；P=0.
97）
。 No dose-response relationship
was detected in dose-response MCP-Mod analysis.
The change in total MDS-UPDRS score relative to baseline at 72 weeks was -0.
9 points (95% CI, -5.
6~3.
8), 0.
6 points (95% CI, -3.
3~4.
4) and -0.
8 points (95%) in the 250mg, 1250mg and 3500mg groups, respectively.
CI，-4.
6~3.
0）
。
Table 1: Primary endpoints at weeks 52 and 72 and secondary endpoints
at week 52 Figure 2: Adjusted mean MDS-UPDRS scores up to weeks 52 and 96
For secondary endpoints, DaT-SPECT imaging showed no clear difference between the placebo group and any dose of Cinpanemab at week 52, and there was no dose-dependent response; Similarly, evidence of efficacy was lacking in all active treatment groups
at week 96.
Fig.
3: In terms of safety of the adjusted mean change in DaT-SPECT striatum binding rate relative to baseline at week 96, 82% and 80% of participants in the treatment and placebo groups reported one or more adverse events, less than 5% of infusion-related adverse reactions were reported in the treatment group, and serious adverse events occurred in 7% of the placebo
group.
Serious adverse events
occurred in 5% of the treatment group.
In summary, this clinical study of patients with early PD did not prove that Cinpanemab treatment can benefit
patients in the three dimensions of clinical symptoms, imaging and quality of life indicators.
Prasinezumab recognizes the C-terminus of α-syn and binds well to monomeric proteins, while Cinpanemab recognizes the N-terminus of α-syn and binds
to it with lower affinity.
The failure of two drugs of the same target is not necessarily a bad thing, at least in the pit of the α-syn target, there should be no more descendants
.
AT THE TIME OF SPARK'S TERMINATION, THE RESEARCHERS SAID: "THE COMPANY'S DECISION IN FEBRUARY 2021 WAS BASED ON RESEARCH ANALYSIS AS OF DECEMBER 31, 2020
.
At the same time, we will apply what we have learned to future research on
Parkinson's disease.
"
Although two clinical studies of targeted drugs against α-syn have been terminated, it may be a good time to switch ideas: can we learn from Alzheimer's disease and find out the reasons behind the emergence of α-syn?" We also look forward to the drugs that can effectively fight PD to meet us as soon as possible
.
Related reading
NEJM is a blockbuster post
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease and has the fastest growing number of patients, with PD affecting about 1% of people over 60 years of age in
high-income countries.
PD is characterized by loss of dopaminergic neurons in the substantia nigra compact, aggregation of α synuclein (α-syn) to form Lewy Body (LBS) and Lewy nerve fibers (Lewy Necrites).
。 Due to the loss of dopaminergic neurons in patients, exogenous dopamine supplementation can significantly improve symptoms, but disease progression cannot be delayed and most patients develop drug
resistance after long-term use.
Therefore, scientists have shifted their research focus to α-syn, working on the development of anti-PD drugs
that target α-syn.
In early August, the New England Journal of Medicine published back-to-back the results
of two clinical trials targeting α-synuclein monoclonal antibody for the drug treatment of early PD.
The two drugs and their counterparts are Prasinezumab and PASADENA and Cinpanemab and SPARK, two highly anticipated α-syn monoclonal antibodies bibifold: After 52 weeks of use, patients in the two experimental groups of patients with movement disorders learned the Unified Parkinson's Disease Rating Scale (MDS-UPDRS).
There was no significant change in scores from baseline compared to the respective controls, and monoclonal antibody therapy did not significantly delay the death
of dopaminergic neurons when single-photon emission computed tomography (SPECT) assessed dopamine transporter levels in the hemispherical putamen.
Figure 1: Prasinezumab and the PASADENA study and the Cinpanemab and SPARK studies were published simultaneously in the New England Journal of Medicine in early August
Prasinezumab and PASADENA
Speaking of failure, this is not the first time Prasinezumab has
faced failure.
As early as 2020, the primary endpoint of alleviating the progression of motor and non-motor symptoms of PD was not met in clinical trials with Prasinezumab as intervention, but there was relief
on exploratory measures and secondary endpoints.
This also provides a premise
for the confirmation of the main endpoint of this study.
A total of 316 participants with early PD were included in this clinical study, which were randomly divided into placebo group, 1500mg/4 weeks Prasinezumab intravenous group and 4500mg/4 weeks Prasinezumab intravenous group
according to 1:1:1.
The primary endpoint was the change in MDS-UPDRS score from baseline at week 52 of medication (higher scores lead to more severe symptoms), and the secondary endpoint was dopamine transporter levels in the hemispherical putamen, which was confirmed
by 123I-iodoflurane SPECT imaging.
At baseline, the mean MDS-UPDRS scores in the placebo group, the 1500 mg group and the 4500 mg group were 32.
0, 31.
5 and 30.
8, respectively, and the increase in the mean MDS-UPDRS score in the three groups after 52 weeks was 9.
4± 1.
2, 7.
4±1.
2 (difference compared with placebo, –2.
0; 80% CI, –4.
2~0.
2; P= 0.
24) and 8.
8±1.
2 (difference compared with placebo, –0.
6; 80% CI, –2.
8~1.
6; P = 0.
72), and spect images also did not differ
significantly between the three groups.
While efficacy was not proven, 19% and 34% of participants in the 1500 mg and 4500 mg groups experienced infusion reactions (compared to 16.
2% in the placebo group) and serious adverse events occurred in 6.
7% and 7.
5% of participants in both groups, respectively (This figure was 4.
8% in the placebo group).
Cinpanemab and SPARK
Like Prasinezumab, the failure of Cinpanemab is not news
.
Information that Cinpanemab did not meet the primary and secondary endpoints in the Phase 2 clinical study SPARK was disclosed
as early as February 2021.
SPARK is a 52-week, multicenter, double-blind, phase 2 trial in which 357 participants with early PD are randomly assigned to placebo (control) or Cinpanemab (at a dose of 250 mg, 1250 mg, or 3500 mg every 4 weeks) in a 2:1:2:2 ratio.
Intravenous infusion, followed by blinded expansion of
the active therapeutic dose for up to 112 weeks.
The primary endpoints of this study were the level of change in MDS-UPDRS scores compared to baseline at weeks 52 and 72, and secondary endpoints included MDS-UPDRS scores at week 96, dopamine transporter single-photon emission computed tomography (DaT-SPECT), intraserum Cinpanemab pharmacokinetics
, and adverse events.
At week 52, the total MDS-UPDRS score in the control, 250 mg, 1250 mg, and 3500 mg groups increased by 10.
8 points and 10.
5 points from baseline, respectively (difference compared with placebo, -0.
3 points; 95% CI, -4.
9~4.
3; P=0.
90), 11.
3 points (difference compared with placebo, 0.
5 points; 95% CI, -3.
3~4.
3; P=0.
80), 10.
9 points (difference compared with placebo, 0.
1 points; 95%CI，-3.
8~4.
0；P=0.
97）
。 No dose-response relationship
was detected in dose-response MCP-Mod analysis.
The change in total MDS-UPDRS score relative to baseline at 72 weeks was -0.
9 points (95% CI, -5.
6~3.
8), 0.
6 points (95% CI, -3.
3~4.
4) and -0.
8 points (95%) in the 250mg, 1250mg and 3500mg groups, respectively.
CI，-4.
6~3.
0）
。
Table 1: Primary endpoints at weeks 52 and 72 and secondary endpoints
at week 52 Figure 2: Adjusted mean MDS-UPDRS scores up to weeks 52 and 96
For secondary endpoints, DaT-SPECT imaging showed no clear difference between the placebo group and any dose of Cinpanemab at week 52, and there was no dose-dependent response; Similarly, evidence of efficacy was lacking in all active treatment groups
at week 96.
Fig.
3: In terms of safety of the adjusted mean change in DaT-SPECT striatum binding rate relative to baseline at week 96, 82% and 80% of participants in the treatment and placebo groups reported one or more adverse events, less than 5% of infusion-related adverse reactions were reported in the treatment group, and serious adverse events occurred in 7% of the placebo
group.
Serious adverse events
occurred in 5% of the treatment group.
In summary, this clinical study of patients with early PD did not prove that Cinpanemab treatment can benefit
patients in the three dimensions of clinical symptoms, imaging and quality of life indicators.
Looking forward to and prospecting
Prasinezumab recognizes the C-terminus of α-syn and binds well to monomeric proteins, while Cinpanemab recognizes the N-terminus of α-syn and binds
to it with lower affinity.
The failure of two drugs of the same target is not necessarily a bad thing, at least in the pit of the α-syn target, there should be no more descendants
.
AT THE TIME OF SPARK'S TERMINATION, THE RESEARCHERS SAID: "THE COMPANY'S DECISION IN FEBRUARY 2021 WAS BASED ON RESEARCH ANALYSIS AS OF DECEMBER 31, 2020
.
At the same time, we will apply what we have learned to future research on
Parkinson's disease.
"
Although two clinical studies of targeted drugs against α-syn have been terminated, it may be a good time to switch ideas: can we learn from Alzheimer's disease and find out the reasons behind the emergence of α-syn?" We also look forward to the drugs that can effectively fight PD to meet us as soon as possible
.
Related reading
- Is β-amyloid a cause or not? The field of Alzheimer's disease has made significant progress
Reference sources:
[1] Pagano G,Taylor KI,Anzures-Cabrera J,et al; PASADENA Investigators; Prasinezumab Study Group.
Trial of Prasinezumab in Early-Stage Parkinson's Disease.
N Engl J Med.
2022 Aug 4; 387(5):421-432.
doi:10.
1056/NEJMoa2202867.
PMID:35921451.
[2] Lang AE,Siderowf AD,Macklin EA,et al.
Trial of Cinpanemab in Early Parkinson's Disease.
N Engl J Med.
2022 Aug 4; 387(5):408-420.
doi:10.
1056/NEJMoa2203395.
PMID:35921450.
[3] Biogen Ditches Parkinson’s Drug After Phase II Study Fails to Show Benefit- style="outline: 0px;max-width: 100%;visibility: visible;box-sizing: border-box !important;overflow-wrap: break-word !important;">
Where can I find more clinical knowledge in neurology?
Come to the "Doctor Station" and take a look 👇
