Effect of prasinezumab on motor features in early PD

Results of the first stage of the PASADENA study showed that treatment with prasinezumab slows motor progression and delays time to clinically meaningful worsening of motor features in early Parkinson’s disease (PD). These results were confirmed in subgroup populations with faster disease progression. Prasinezumab had a favourable safety profile.

Prasinezumab is the first monoclonal antibody that binds aggregated alpha-synuclein at the C-terminus with high selectivity, and is more effective in preclinical models than N-terminal antibodies.

PASADENA (NCT03100149) is a randomised, double blind, placebo-controlled, phase 2 study with 3 stages. In stage 1, 316 patients with early PD were randomised for 52 weeks to placebo, prasinezumab 1,500 mg, or prasinezumab 4,500 mg [1]. In stage 2, the original placebo group is re-randomised to prasinezumab 1,500 mg or 4,500 mg. In stage 3, all eligible patients will receive open-label prasinezumab 1,500 mg for up to 60 months. The primary endpoint is change in Movement Disorder Society-Unified Parkinson’s disease Rating Scale (MDS-UPDRS) total score (sum of parts I, II, and III) after 52 weeks.

A real-world study previously showed that over a 1-year period, only progression in MDS-UPDRS part III (motor examination) is clinically meaningful [2]. In PASADENA as well, MDS-UPDRS progression in parts I (non-motor experience of daily living) and II (motor experience of daily living) remained below the threshold for clinical meaningfulness. Taken together, the primary endpoint was not met. MDS-UPDRS total scores were:

• -1.30 (80% CI -3.18 to 0.58) for pooled doses versus placebo;
• -2.02 (80% CI -4.21 to 0.18) for prasinezumab 1,500 mg;
• -0.62 (80% CI -2.82 to 1.58) for prasinezumab 4,500 mg.

MDS-UPDRS part III did give a signal of efficacy:

• -1.44 (80% CI -2.83 to -0.06) for pooled treatment versus placebo;
• -1.88 (80% CI -3.49 to -0.27) for prasinezumab 1,500 mg;
• -1.02 (80% CI -2.64 to 0.61) for prasinezumab 4,500 mg.

MDS-UPDRS part III site rating, MDS-UPDRS part III bradykinesia subscore, digital motor endpoints, and time to worsening of motor symptoms supported this efficacy signal. Prasinezumab delayed time to clinically meaningful worsening of motor signs (≥5 points increase in MDS-UPDRS part III) versus placebo (pooled HR 0.84).

Subgroup analyses revealed that slowing of clinical decline was more evident in groups with faster disease progression, namely patients treated with a MAO-B inhibitor and patients with a diffuse malignant sub-phenotype (n=59) versus mild motor predominant (n=106) and intermediate (n=151) sub-phenotypes. There were no life-threatening adverse events or immunogenicity concerns.

1. Pagano G, et al. Phase II PASADENA Part one Week 52 results: Evaluating safety and efficacy of prasinezumab in early Parkinson’s. OPR-104, EAN 2021 Virtual Congress, 19–22 June.
2. Simuni T, et al. Mov Disord. 2018;33(5):771-82.

 

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Posted on 18 August 202117 May 2024