Take home lessons from the failures of the two Parkinson's monoclonal antibody studies
Two randomized randomized monoclonal antibody studies failed in recent trials published in the New England Journal of Medicine. What are the take home points for persons with Parkinson’s? In this month’s blog we will discuss. Below are the references from the articles:
Lang AE, Siderowf AD, Macklin EA, Poewe W, Brooks DJ, Fernandez HH, Rascol O, Giladi N, Stocchi F, Tanner CM, Postuma RB, Simon DK, Tolosa E, Mollenhauer B, Cedarbaum JM, Fraser K, Xiao J, Evans KC, Graham DL, Sapir I, Inra J, Hutchison RM, Yang M, Fox T, Budd Haeberlein S, Dam T; SPARK Investigators. Trial of Cinpanemab in Early Parkinson's Disease. N Engl J Med. 2022 Aug 4;387(5):408-420. doi: 10.1056/NEJMoa2203395. PMID: 35921450.
Pagano G, Taylor KI, Anzures-Cabrera J, Marchesi M, Simuni T, Marek K, Postuma RB, Pavese N, Stocchi F, Azulay JP, Mollenhauer B, López-Manzanares L, Russell DS, Boyd JT, Nicholas AP, Luquin MR, Hauser RA, Gasser T, Poewe W, Ricci B, Boulay A, Vogt A, Boess FG, Dukart J, D'Urso G, Finch R, Zanigni S, Monnet A, Pross N, Hahn A, Svoboda H, Britschgi M, Lipsmeier F, Volkova-Volkmar E, Lindemann M, Dziadek S, Holiga Š, Rukina D, Kustermann T, Kerchner GA, Fontoura P, Umbricht D, Doody R, Nikolcheva T, Bonni A; PASADENA Investigators and Prasinezumab Study Group. Trial of Prasinezumab in Early-Stage Parkinson's Disease. N Engl J Med. 2022 Aug 4;387(5):421-432. doi: 10.1056/NEJMoa2202867. PMID: 35921451.
What are monoclonal antibodies?
An antibody can be constructed by scientists to target any protein in the brain or nervous system. Antibodies targeting aggregated α-synuclein in Parkinson’s disease have been ‘hot’ as potential treatments.
What is Cinpanemab?
Cinpanemab is a human-made monoclonal antibody. The antibody binds α-synuclein. It targets the N-terminal portion of α-synuclein. It has a lower binding affinity for ‘monomeric α-synuclein.’
There was a 52-week multi-center double-blind phase 2 trial. The primary outcome was the change from baseline in the Movement Disorder Society UPDRS total score. The study was terminated early for lack of efficacy. Imaging endpoints also did not change.
What is Prasinezumab?
Prasinezumab is another monoclonal antibody. It recognizes the C-terminal of α-synuclein. It strongly binds to aggregated and monomeric α-synuclein.
The study for this antibody was a phase 2 randomized clinical trial. The primary outcome was a change score calculated from baseline to one year on the MDS-UPDRS parts I, II, and III. There were no differences in imaging or other outcomes.
Why did both trials fail?
Neither antibody improved clinical outcomes or altered disease progression.
The imaging analysis did not show any changes of consequence. Are we targeting Lewy bodies and α-synuclein too late in the pathogenic process?
Cerebrospinal fluid biomarkers were not measured.
No assessment of target engagement.
Studies suggest that α-synuclein aggregation is neither necessary nor sufficient for parkinsonism or for neurodegeneration.
If the Lewy body pathology represents the end of ‘functional α-synuclein,’ this could explain the failures of both NEJM monoclonal antibody studies.
Should we explore new avenues?
Many in the field have discussed this possibility of exploring new avenues. If neurodegeneration is about ‘loss,’ and normal α-synuclein is important to the human condition, then maybe we need a fresh approach. Alberto Espay from the University of Cincinnati has said that Lewy pathology represents the ‘tombstones of previously normal, monomeric soluble α-synuclein.’ Once proteins polymerize into Lewy bodies it is likely too late. This may inform the reason(s) why the monoclonal antibodies and future vaccine studies may fail.
Dr. Michael Okun and Dr. Indu Subramanian are the doctors providing the content for the blog.
Jonny Acheson is the parkinsonsecrets.com artist.