Two strikes and monoclonal antibodies for early-stage Parkinson’s disease?

Similarly designed Phase II trials of two alpha-synuclein-targeted biologics have dashed hopes for disease-modifying monoclonal antibody drugs in early Parkinson’s disease.

In the SPARK study, cinpanemab met neither of the two primary endpoints for change in the sum of scores in Parts I, II, and III of the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) total score. reported Tien Dam, MD, of drug developer Biogen in Cambridge, Massachusetts, and colleagues.

There was no significant change from baseline to week 52 (change from placebo: -0.3 point out of a possible 236 in the 250 mg group, 0.5 point in the 1,250 mg group, and 0.1 point in the 3,500 -mg group) or at week 72 (difference in cinpanemab initiation at baseline vs. week 52: -0.9, 0.6, and -0.8 points, respectively).

In the PASADENA study, prasinezumab also did not significantly change the same endpoint from baseline to week 52 (change from placebo: -2.0 points in the 1,500 mg group and -0.6 points in the 4,500 mg group) , reported Gennaro Pagano, MD , PhD, from the Roche Innovation Center Basel in Switzerland, and colleagues. A delayed start cohort yielded similarly negative results.

Both groups concluded in the jointly published studies that the effect is not meaningful for imaging measures overall New England Journal of Medicine.

The results were “more than disappointing and certainly have no impact on current practice,” noted Alan Whone, PhD, of the University of Bristol and Southmead Hospital in Bristol, England, in an accompanying editorial.

“The negative data did not appear to have deterred PASADENA’s sponsor from initiating a Phase 2b trial, although overall it seems likely that the evidence marks the end of the road for monoclonal antibodies in the treatment of early Parkinson’s disease,” he wrote.

Biogen announced that it would stop developing cinpanemab.

Both investigational substances target the aggregated form of the protein alpha-synuclein, which is thought to be the major cause of the pathogenesis of Parkinson’s disease. Both are humanized monoclonal antibodies that selectively bind to aggregated alpha-synuclein, which targets prasinezumab at the C-terminus of the protein and cinpanemab at the N-terminus.

Prasinezumab had a significant benefit in a secondary endpoint — slower progression with the lower dose in Part III of the MDS-UPDRS, reflecting the physician-performed motor assessment, Pagano’s group found.

Whone warned that the secondary endpoints were not corrected for multiple comparisons, “and therefore no conclusions can be drawn.”

“Nevertheless, this should not preclude the possibility that the same or similar agents may still be successful in prodromal Parkinson’s disease or in genetic forms of the disease, or that alternative mechanisms to affect aggregated alpha-synuclein may be beneficial,” wrote he.

A larger question Whone has raised is whether the “pathetic lack of understanding” of disease-modifying drugs for Parkinson’s disease is due to misleading preclinical research, current clinical trial designs yielding Type II errors, or both.

“For PASADENA and the SPARK study, the former explanation seems more likely, but the latter explanation remains possible; if true, it could mean outcome measurements should be more sophisticated and move into the digital age,” he wrote.

SPARK enrolled 357 patients with early-stage Parkinson’s disease who were randomized to receive intravenous placebo or cinpanemab at a dose of 250 mg, 1,250 mg or 3,500 mg every 4 weeks for 52 weeks, followed by a dose-blind extension phase for active treatment of up to 112 weeks .

The PASADENA study enrolled 316 patients with early-stage Parkinson’s disease who were randomized to receive placebo or prasinezumab at a dose of 1,500 mg or 4,500 mg intravenously every 4 weeks for 52 weeks. Part 2 of the study included a delayed-start cohort that received placebo for the first 52 weeks and switched to prasinezumab at a dose of 1,500 or 4,500 mg from weeks 56 to 104.

Both studies enrolled patients in North America and Europe, with Israel also enrolled in SPARK.

Despite the negative results, Whone wrote: “Should anyone want to try again – and it remains possible – there is a time lag between clearance of aggregated alpha-synuclein and neuronal sparing, and that a significantly longer trial duration may prove more.” successfully – both agents appeared to be relatively safe and raised no concerns about immunogenicity.”