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Two Strikes and Monoclonal Antibodies Are Out for Early Parkinson's?

— Failure of two agents in two phase II trials could spell the end for one avenue of treatment

Ƶ MedicalToday
A computer rendering of monoclonal antibodies.

Similarly designed phase II trials of two investigational alpha-synuclein targeted biologics dashed hopes for disease-modifying monoclonal antibody drugs in early-stage Parkinson's disease.

In , cinpanemab failed to hit either primary endpoint for change in the sum of scores on 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.

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

In , prasinezumab also did not significantly change the same endpoint from baseline to week 52 (change vs 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, of the Roche Innovation Center Basel in Switzerland, and colleagues. A delayed-start cohort yielded similarly negative results.

The effect wasn't meaningful overall for imaging measures, both groups concluded in the studies published together in the New England Journal of Medicine.

The results were "more than disappointing and certainly have no implications for current practice," noted Alan Whone, PhD, of the University of Bristol and Southmead Hospital in Bristol, England, in an .

"The negative data have apparently not deterred the sponsor of PASADENA from commencing a phase 2b trial, although it 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," he wrote.

Biogen it was discontinuing development of cinpanemab.

Both investigational agents target the aggregated form of the protein alpha-synuclein, considered to be a main culprit in the pathogenesis of Parkinson's disease. Both are a humanized monoclonal antibody that selectively binds aggregated alpha-synuclein, which prasinezumab grabs at the C-terminal of the protein and cinpanemab at the N-terminal.

Prasinezumab had one significant benefit in a secondary endpoint -- slower progression with the lower dose on part III of the MDS-UPDRS, reflecting clinician-conducted motor examination, Pagano's group noted.

Whone cautioned that the secondary endpoints were not corrected for multiple comparisons, "and hence no conclusions can be drawn from them."

"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 alpha-synuclein may be beneficial," he wrote.

A bigger question that Whone raised is whether the "pitiful lack of realization" of disease-modifying agents for Parkinson's disease are due to misleading preclinical research, current clinical trial designs delivering type II errors, or both.

"For PASADENA and the SPARK trial, it seems that the former explanation is more likely, but the latter explanation remains possible; if true, that could imply that outcome measures should be more sophisticated and move into the digital age," he wrote.

SPARK included 357 patients with early Parkinson's disease randomized to IV placebo or cinpanemab at a dose of 250 mg, 1,250 mg, or 3,500 mg every 4 weeks for 52 weeks, followed by an active-treatment dose-blinded extension period for up to 112 weeks.

The PASADENA trial involved 316 patients with early-stage Parkinson's disease randomized to receive IV placebo or prasinezumab at a dose of 1,500 mg or 4,500 mg every 4 weeks for 52 weeks. Part 2 of the trial involved a delayed-start cohort receiving placebo for the first 52 weeks who switched to prasinezumab at a dose of 1,500 or 4,500 mg from weeks 56 through 104.

Both trials enrolled patients in North America and Europe, with the addition of Israel in SPARK.

Despite the negative findings, Whone wrote, "should someone wish to try again from scratch -- and it does remain possible that there is a temporal delay between clearance of aggregated alpha-synuclein and neuronal sparing and that a considerably longer trial duration may prove more successful -- both agents seemed to be relatively safe and did not arouse immunogenicity concerns."

Disclosures

SPARK was supported by Biogen.

PASADENA was supported by F. Hoffmann-La Roche and Prothena Biosciences.

Dam disclosed stock and employment with Biogen.

Pagano disclosed stock and employment with F. Hoffmann-La Roche.

Whone disclosed personal fees from Vivifi Biotech.

Primary Source

New England Journal of Medicine

Lang AE, et al "Trial of cinpanemab in early Parkinson's disease" N Engl J Med 2022; DOI: 10.1056/NEJMoa2203395.

Secondary Source

New England Journal of Medicine

Pagano G, et al "Trial of prasinezumab in early-stage Parkinson's disease" N Engl J Med 2022; DOI: 10.1056/NEJMoa2202867.

Additional Source

New England Journal of Medicine

Whone MA "Monoclonal antibody therapy in Parkinson's disease -- the end?" N Engl J Med 2022; DOI: 10.1056/NEJMe2207681.