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Monoclonal antibodies disappoint in early Parkinson’s disease

By Shreeya Nanda, medwireNews Reporter

Two monoclonal antibodies targeting aggregated α-synuclein have failed to improve clinical or imaging measures of Parkinson’s disease progression in the early-stage setting.

The results of the two phase 2 trials – SPARK by Tien Dam (Biogen, Cambridge, Massachusetts, USA) and colleagues and PASADENA by Gennaro Pagano (Roche Innovation Center Basel, Switzerland) and team – are published in The New England Journal of Medicine with an accompanying editorial by Alan Whone (University of Bristol, UK).

The editorialist says: “[I]t does seem likely that the evidence in aggregate marks the end of the road for monoclonal antibodies in the treatment of early Parkinson’s disease.

“Still, this should not dismiss the possibilities that success may yet be achieved with the same or similar agents in prodromal Parkinson’s disease or in genetic forms of the disorder or that alternative mechanisms to affect aggregated α-synuclein may be beneficial.”

The SPARK trial investigated cinpanemab, a monoclonal antibody that recognizes the N-terminal of α-synuclein, in 357 individuals aged 40–80 years (mean, 60 years) who scored 2.5 or less on the modified Hoehn and Yahr scale of Parkinson’s disease progression and had not received prior treatment.

Participants were randomly assigned to receive intravenous cinpanemab 250 mg, 1250 mg or 3500 mg or placebo every 4 weeks during the initial 52-week double-blind phase of the trial. This was followed by an extension period of up to 60 weeks in which cinpanemab-treated patients continued at the assigned dose, while those in the placebo group initiated cinpanemab at one of the three doses.

The co-primary endpoint of the change from baseline in the Movement Disorder Society–sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) total score at week 52 did not differ significantly between the groups, with adjusted mean increases (indicating worsening disease) of 10.5, 11.3 and 10.9 points for the cinpanemab 250, 1250 and 3500 mg groups, respectively, versus 10.8 points for the placebo group.

The findings were similar for the other primary endpoint – the change from baseline to week 72 in the MDS-UPDRS total score. In this case, the adjusted mean changes for the patients who received cinpanemab from the beginning (ie, early start) were a respective 6.0, 7.5 and 6.2 points for the 250, 1250 and 3500 mg doses and 7.0 points for those who switched to any cinpanemab dose from placebo at week 52 (ie, delayed start).

The study was stopped early “owing to lack of efficacy” after the results of the analysis at week 72 became available, say the researchers.

The cinpanemab and placebo arms were also comparable with regard to secondary endpoints and imaging biomarkers, with single-photon emission computed tomography imaging of the dopamine transporter (DaT-SPECT) showing “no substantial differences” between cinpanemab- and placebo-treated participants at week 52, report Dam and co-workers.

And they conclude: “The results of our trial suggest that targeting extracellular α-synuclein with an N-terminal– directed antibody as monotherapy may be insufficient to slow the progression of disease.”

In the second trial – PASADENA – 316 treatment-naïve patients (mean age, 59.9 years) with a score of 1 or 2 on the modified Hoehn and Yahr scale were randomly assigned in a double-blind fashion to receive intravenous prasinezumab, which binds the C-terminal of α-synuclein, at a dose of 1500 or 4500 mg (3500 mg for those with a bodyweight <65 kg) or placebo every 4 weeks for 52 weeks. At this timepoint, placebo-treated participants were randomly allocated to one of the two doses of prasinezumab, and the trial continued for a further 52 weeks.

As in the SPARK study, the primary endpoint was the change in the MDS-UPDRS total score from baseline to week 52, and again, there were no significant differences between the arms, at adjusted mean increases of 7.4, 8.8 and 9.4 points with prasinezumab 1500 mg, prasinezumab 4500 mg and placebo, respectively.

With regard to secondary endpoints, Pagano et al highlight that “[f]or each of the three MDS-UPDRS parts (I, II, and III), the 80% confidence intervals for differences between the active-treatment groups and the placebo group to week 52 included zero for both doses, with the exception of the 1500-mg dose for MDS-UPDRS part III.”

But they caution that there was no adjustment for multiple comparisons, “so no conclusion can be drawn from this finding.”

In the PASADENA trial also, there was no significant improvement in measures of activities of daily living or imaging biomarkers at week 52 with receipt of the monoclonal antibody, and the early- and delayed-start cohorts were comparable for all assessed endpoints at week 104.

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