neuraldegenerative diseases are a type of neurodegenerative disease caused by the gradual loss of structure or function or even death of neurons Disorders of nervous system functiondisorders. With the aging of the population, the incidence of neurodegenerative diseases continues to increase, bringing a serious burden to families and society. Common neurodegenerative diseases mainly include Alzheimer’s disease (AD) and Parkinson’s disease (PD).
Due to the complexity of the nervous system structure, it is difficult to develop effective therapeutic drugs, and the disease progression of countless patients is still not effectively controlled, serious affect their daily lives. In order to help patients delay disease progression and improve their quality of life, Roche looks for effective disease-modifying therapies (DMTs) from the pathogenesis of AD and PD. After years of unremitting efforts, certain progress has been made: Gantenerumab can significantly reduce amyloid beta plaques (Aβ) in the brains of AD patients, and high doses may produce more significant clinical effects. Therefore, Roche has further developed GRADUATE- 1 and GRADUATE-2 studies; in addition, Prasinezumab has the potential to improve motor symptoms and delay disease progression in patients with early-onset disease in the treatment of PD, and related research is also ongoing.
The fully human monoclonal antibody Gantenerumab binds and clears Aβ, alleviates the decline of cognitive function in AD patients , Aβ) deposition is an important mechanism of AD pathogenesis. After a large amount of neurotoxic Aβ deposition, it will trigger synaptic dysfunction and lead to dementia.
For this mechanism, Roche has developed a fully human monoclonal targeting Aβ Antibody Gantenerumab, the study found that the high affinity of Gantenerumab to Aβ deposits can effectively reduce Aβ deposition in microglia (Figure 1); in addition, Gantenerumab was also observed in positron emission tomography (PET) by Fcγ Receptor-mediated phagocytosis of microglia not only inhibits the accumulation of amyloid plaques, but also has a certain clearance effect1,2 (Figure 2).
Blue), Gantenerumab (red) and Aβ plaques (green) with triple staining labeling plots
image after Decreased SUVR (amyloid plaque reduction) on PET after Gantenerumab treatment
Note: SUVR-normalized uptake value ratio
Not only that, the previous SCarletRoAD study also found that the effect of Gantenerumab in reducing amyloid protein and reducing the rapid disease progression in AD patients was positively related to the drug dose (Fig. 3), follow-up correlation analysis found that the clinical effect of high-dose Gantenerumab treatment may be better1,2.
Figure 3. Gantenerumab reduces amyloid and reduces cognitive function in patients with AD The relationship between rapid progression effect and dose Note: ADAS-Cog13 scale was used to assess the progress of cognitive function in AD patients
In addition, the study found that after Gantenerumab treatment, subjects continued to reduce amyloid, as observed by PET, 52% of subjects had amyloid below SUVR after 2 years of treatment, while 80 % of subjects had amyloid below positive threshold after 3 years of high-dose therapy1,2 (Figure 4).
Sustained amyloid reduction effect of
It was concluded from the above studies that Gantenerumab produced a sustained reduction in amyloid at a certain dose. In order to further explore the efficacy and safety of Gantenerumab, GRADUATE conducted experiments based on previous studies. Followed by PostGraduate will continue to explore the long-term safety and efficacy of Gantenerumab.
GRADUATE-1 and GRADUATE-2 are two multicenter, randomized, double-blind, placebo Controlled studies, after 10 years of precipitation and optimization, GRADUATE-1 and GRADUATE-2 have established fairly stable datasets. These 2 studies included eligible subjects from 31 countries in Asia, Australia, Europe, North and South America (Table 1, Table 2), subcutaneously administered at a dose of 1020 mg/month of Gantenerumab , for 27 months, to evaluate the efficacy and safety of Gantenerumab in patients with early-stage (prodromal to mild) AD.
Table 1. Subjects in GRADUATE-1 and GRADUATE-2 studies have similar disease conditions< /p>
Table 2. APOE>ɛ4 and biomarker screening in GRADUATE-1 and GRADUATE-2 studies
After enrollment, subjects were randomly divided into experimental group (administration group) and control group (placebo group). Regardless of apolipoprotein Eε4 status, the drug dose was titrated to the target dose of 1020 mg/month over 9 months. After 27 months of continuous administration, the changes in the total score of the primary endpoint of the Clinical Dementia Rating Scale compared with the baseline level and the changes in the secondary endpoints of body fluids and imaging biomarkers were observed.
GRADUATE-1 and GRADUATE-2 studies not only used FCSRT to assess subjects’ disease progression, but also It also allows subjects to receive subcutaneous injections at home by a skilled nursing staff. Study results are expected in the fourth quarter of 2022.
Studies above:Baseline characteristics of the GRADUATE studies span>Published by the 2022 American Academy of Neurology (AAN) Annual Meeting.
1
In addition, in order to continue evaluating the long-term safety of Gantenerumab and effectiveness, the PostGraduate study has also been launched. The study enrolled 2032 eligible patients (who had completed GRADUATE-1 or GRADUATE-2 studies) on follow-up therapy: subcutaneous Gantenerumab at a dose of 510 mg/2 weeks (Q2W) for 2 years (note that 120 mg , 225mg, 510mg/4 weeks of administration doses were gradually increased titrated dose). The dosing schedule is kept confidential to the subjects. The safety and tolerability of the drug were mainly assessed by observing and recording adverse drug events, physical examination, vital signs, laboratory tests, suicidal tendencies, amyloid-related imaging abnormalities, and injection site reactions, followed by the observation of pharmacokinetics pharmacology, antidrug antibodies, and longitudinal biomarkers to assess drug efficacy (assessing consistency with the GRADUATE study, including patient cognition, function, quality of life, and caregiver burden). Detailed data will be announced later.
Studies above:Post Graduate Open-Label Rollover Study< span>Published by AAN (2022).
(scan the QR code to view)2
Prasinezumab targets the pathogenesis of PD to relieve motor symptoms in patients, and DMT therapy brings new hope for disease treatment
From the current treatment of PD, the therapy for the pathogenesis of PD is still blank, lack of root causes. Drugs that can effectively alleviate disease progression. Existing treatments cannot significantly alleviate disease progression, and with the death of neurons and synapses, poor efficacy will inevitably occur in the long-term. p>
Prasinezumab is a humanized monoclonal antibody targeting α-synuclein (α-syn), while α Abnormal accumulation of -syn in the substantia nigra-striatal region of the PD patients is the main pathology responsible for the death of dopaminergic neurons. Prasinezumab reduced neuronal and synaptic loss in pre-experiments, and increased the accumulation of α-syn exhibited inhibitory effect (Figure 5).
Figure 5. Prasinezumab inhibits α-syn aggregation and protects neurons
In order to evaluate Prasinezumab in patients with early PD efficacy and safety, Roche conducted the PASADENA Part 1 study, which showed that compared with placebo, patients treated with Prasinezumab had a Symptoms were alleviated (Figure 6), and showed good safety (Table 3).
Fig. 6. Prasinezumab
Table 3. Prasinezumab Adverse Events Statistics
Not only that The effect of prasinezumab in improving motor symptoms in patients with early PD was further confirmed in the follow-up PASADENA part 2 study.
This study included patients with early stage PD (ePD) (diagnosed by screening for ≤2 years or Hoehn & Yahr classification) Phase I-II), randomly divided into 2 groups, one group received Prasinezumab intravenous injection (dosing according to body weight), 4 weeks/time for 104 weeks (early initiation group); the other group continued to inject placebo for 52 weeks After that, intravenous injection of Prasinezumab was started again for 52 weeks (Yanqi group).
The study found that the early start group had lower MDS-UPDRS part III scores than the Yanqi group (see Figure 7). ). Among them, there was a significant difference between the early start group and the late start group in the score of bradykinesia (see Figure 8).
Comparison of early start group Motor symptoms
Figure 8. There is a significant difference between the early start group and the delayed group in the bradykinesia scores
The above study: A 104-week delayed-start analysis of PASADENA was published by AAN (2022).
(scan the QR code to view)3
In the PASADENA study, Prasinezumab showed the potential to delay the progression of motor symptoms in patients with ePD, so the follow-up study PADOVAIIb will further evaluate the efficacy and safety of Prasinezumab in the symptomatic treatment of patients with ePD Looking forward to the release of follow-up research results.
Summary
AD and PD are both common neurodegenerative diseases, and the number of patients It should not be underestimated, once the disease occurs, the damage to the patient’s cognitive function is serious. A series of researches on the pathogenesis are in full swing. Among them, Roche has never stopped exploring, and has always focused on the pathogenesis of the disease. Unremittingly explore safe and effective DMT treatment drugs, hoping to effectively alleviate disease progression, improve patients’ quality of life, and even help patients return to normal life. Fully humanized monoclonal antibody Gantenerumab targeting Aβ and humanized monoclonal antibody targeting α-syn Anti-Prasinezumab is the answer given by Roche at this stage.
References:
1. Christopher Lane, et al. Baseline Characteristics of the GRADUATE Studies: Phase III Randomized, Placebo-Controlled Studies Investigating Subcutaneous Gantenerumab in Participants with EarlyAlzheimer’s Disease. Presented at AAN 2022, Seattle, WA, USA. (P16 .005)
2. Christopher Lane,et al. PostGraduate Open-label Rollover Study: Evaluation of SubcutaneousGantenerumab Long-term Safety, Tolerability, and Efficacy in Participants with Alzheimer’s Disease. Presented at AAN 2022, Seattle, WA,USA. (P6.002 )
3.Gennaro Pagano,etal. A 104-week delayed-start analysis of PASADENA (Phase II study evaluating the safety and efficacy of prasinezumab in early Parkinson’ disease). Presentedat AAN 2022, Seattle, WA,USA. (S16.008)
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