NEJM (IF=176) 2 articles!

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Aggregated α-synuclein plays an important role in the pathogenesis of Parkinson's disease

On August 4, 2022, Roche Pharmaceuticals Gennaro Pagano et al.

A total of 316 participants participated; 105 were assigned to receive placebo, 105 to receive 1500 mg of prasinezumab, and 106 to receive 4500 mg of prasinezumab

In addition, Tien Dam and other teams from Biogen Pharmaceuticals published a research paper titled "Trial of Cinpanemab in Early Parkinson's Disease" online in the internationally renowned medical journal NEJM.

Aggregated α-synuclein (α-synuclein) is considered to be a major feature of the pathogenesis of Parkinson's disease
.

Prasinezumab is a humanized monoclonal antibody that selectively binds alpha-synuclein aggregated at the C-terminus of the protein
.

In a mouse model of alpha-synucleinopathies, the mouse form of prasinezumab reduces the accumulation of alpha-synuclein aggregates and synapse loss in neurons, reverses astrogliosis and microglial Plasma cell proliferation and improved functional performance in the water maze and horizontal beam tests
.

In a phase 1 trial, prasinezumab demonstrated brain penetration and resulted in a dose-dependent reduction from baseline in free serum alpha-synuclein levels in healthy volunteers and Parkinson's disease patients
.

The current Phase 2 trial of an anti-alpha-synuclein antibody in early-stage Parkinson's disease (PASADENA) is a three-part randomized trial evaluating low-dose (1500 mg) and high-dose (4500 mg) prasinezumab in early Efficacy and safety in patients with Parkinson's disease
.

Here, the study reports results from a 52-week, double-blind, placebo-controlled portion (Part 1) and an exploratory additional 52-week blind extension (Part 2) in which all participants received active treatment
.

Part 3 is an ongoing 5-year open-label extension
.

In this phase 2 trial, participants with early-stage Parkinson's disease were randomized 1:1:1 to receive intravenous placebo or prasinezumab at a dose of 1500 mg or 4500 mg every 4 weeks for 52 weeks
.

The primary endpoint was the Movement Disorders Society-sponsored Unified Parkinson's Disease Rating Scale, Revised (MDS-UPDRS; range, 0 to 236, with higher scores indicating greater impairment)
.

Secondary endpoints included dopamine transporter levels in the hemispheric putamen measured by123I-iodoflurane single photon emission computed tomography (SPECT)
.

A total of 316 participants participated; 105 were assigned to receive placebo, 105 to receive 1500 mg of prasinezumab, and 106 to receive 4500 mg of prasinezumab
.

Baseline mean MDS-UPDRS scores were 32.
0 in the placebo group, 31.
5 in the 1500-mg group, and 30.
8 in the 4500-mg group, and the mean (±SE) change from baseline to Week 52 in the placebo group was 9.
4±1.
2, 1500-mg 7.
4±1.
2 in the 4500-mg group (difference from placebo, –2.
0; 80% confidence interval [CI], –4.
2 to 0.
2; P=0.
24) and 8.
8±1.
2 in the 4500-mg group (difference from placebo, – 0.
6; 80% CI, –2.
8 to 1.
6; P=0.
72)
.

 Dopamine transporter levels on SPECT were not significantly different between the active treatment and placebo groups
.

Results for most clinical secondary endpoints were similar in the active treatment and placebo groups
.

 Serious adverse events occurred in 6.
7% of participants in the 1500 mg group and 7.
5% in the 4500 mg group; infusion reaction rates were 19.
0% and 34.
0%, respectively
.

In conclusion, the study found that prasinezumab treatment had no meaningful effect on global or radiographic measures of Parkinson's disease progression compared with placebo and was associated with infusion response
.
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