Immunotherapy Update for Parkinson’s Disease

Update on immunotherapy for Parkinson’s disease: Pasadena Phase II completed

David Miller and Nate McMullen

This post is presented in two parts: an update from Nate regarding current immunologIc approaches to Parkinson’s, and the first person accounting of participation in the 2-year Phase II Pasadena monoclonal antibody drug trial from David.
The authors thank the entire team at the Parkinson Wellness Recovery practice in Tucson Arizona for their commitment to excellence in the care of people with Parkinson’s.

One of the major therapeutic approaches for treating Parkinson’s disease is immunotherapy. Immunotherapy uses a patient’s own immune system in the form of antibodies to fight disease. Antibodies are small proteins that bind to antigens. Antigens are any substance recognized as “foreign” by our immune system such as bacteria, viruses, etc. The binding of antibodies to antigens is a fundamental mechanism by which the body protects itself from foreign substances. Once bound by antibodies, antigens are targeted for attack and destruction by another type of white blood cell called a macrophage. Antibodies are produced and secreted by a type of white blood cell (there are several types) called B-lymphocytes. B-lymphocytes are produced in the bone marrow and are released to circulate in the bloodstream.

In the case of Parkinson’s disease, antibodies are developed experimentally to recognize and bind to abnormal forms of the protein alpha-synuclein which is the major component of Lewy Bodies, the cellular hallmark of Parkinson’s disease. In theory, once alpha-synuclein is bound by antibodies, the patient’s own immune system can assist to “clear”, or at least lessen, the abnormal protein. This is especially important because of the evidence of the cell-to-cell (prion-type) transfer of “abnormal” alpha-synuclein as a basis of disease spread. Alpha-synuclein, released from cells when they die and released from the cell membrane (called exocytosis) is present in the extracellular fluid surrounding neurons, cerebrospinal fluid (CSF) as well as the blood. It is extracellular alpha- synuclein that is the target of antibody therapy. That is because the blood brain barrier generally allows very poor penetration of antibodies into the brain (Banks et al, 2007). Furthermore, Lewy Bodies are intracellular structures and therefore are likely NOT the primary target of this immunotherapy.

The development of antibodies against alpha-synuclein can occur both actively and passively (Valera & Masliah, 2013). Active immunization takes place by injecting the antigen (in this case abnormal alpha-synuclein) into a patient and stimulating their own immune system to produce antibodies. This is the approach taken by AFFIRIS. There are serious dangers to this technique. A dreaded complication is when immunotherapy leads to the creation of antibodies directed against normal tissues. Accidently targeting “good” proteins can generate an autoimmune reaction in which the immune system targets self-antigens leading to brain inflammation (Valera & Masliah, 2013). In passive immunization, antibodies to alpha-synuclein are produced, purified in the lab, and then are injected into the patient, an approach used by Biogen and Prothena. Since the half-life of antibodies in the bloodstream is limited, passive methods require repeated injections during treatment sometimes over several years (Chatterjee & Kordower, 2019).

Currently, there are six immunotherapeutic agents being tested in Parkinson’s patients (Chatterjee and Kodower 2019). One company Prothena (and Roche) have recently announced the completion of their two-year Phase II trial of antibody PRX002. An attractive feature of Prothena’s PRX002 is that it is based on published, peer-reviewed research going back many years and led by Dr. E. Masliah who heads up the Experimental Neuropathology Laboratory at UCSD, (Masliah et al, 2011; Games et al, 2013; Games et al., 2014). Experimental studies of this antibody in animal models has shown that passive immunization with antibodies against alpha-synuclein promotes clearance of alpha-synuclein aggregates from neurons (Valera & Masliah, 2013; Masliah et al, 2011)! Their first clinical trial to determine safety, tolerability, and immunogenicity of PRX002 was completed in 2015. This study, carried out in 40 healthy subjects, revealed that PRX002 is safe and well-tolerated. Subjects receiving the PRX002 antibody (by i.v. injection) showed a 96 % reduction in blood levels of alpha-synuclein. Surprisingly, reduction of alpha-synuclein was shown to be robust, rapid and dose-dependent after just a single dose. (Prothena site)

The following is a summary of the Phase II results from MJ FOX:

“PASADENA is a Phase II study of prasinezumab (PRX002) a therapy being studied for its potential to slow the progression of Parkinson’s disease. Phase II studies are typically designed to learn about a medicine’s safety and to estimate its potential benefit. Phase II studies test new medicines in fewer people with Parkinson’s before larger Phase III studies are initiated to ultimately confirm safety and efficacy that is required before a new therapy can be approved. While the study did not reach the prespecified level of statistical significance for the primary endpoint, it did show signals of efficacy on multiple prespecified secondary and exploratory clinical endpoints — predetermined measures that were also included to evaluate efficacy as part of the study. The study also demonstrated that prasinezumab was generally well-tolerated. At this time, we are continuing to evaluate the data to determine the possible next steps, including further clinical studies.”

We are fortunate to have a PWR gym member (David Miller) who has served in the recently completed Phase II trial. What follows is his report of this experience.

My experiences with the PASADENA Phase II clinical (drug) trial.

David J. Miller 5/9/20

“I think you have early Parkinson’s”. I first heard these words about three years ago at my visit with a neurologist. Some six months later, following a visit to a movement disorder specialist and undergoing a DaT SPECT scan (or DatScan), the diagnosis was confirmed.’

At the time of diagnosis (fall 2017) I was just turning 66, and recently retired from a career in academics as a Physical Therapy faculty member and Health Sciences Dean. I sought the wise counsel of one of the smartest people I know, my wife Nancy. We quickly agreed to explore options to participate in a Parkinson’s focused clinical trial. I had several motives for seeking out and ultimately enrolling in the PASADENA clinical drug trial. My inwardly focused motivation was the possibility of receiving a new cutting-edge medication prior to the medication being available commercially. I did acknowledge that I might not be receiving the medication for the first year, and I also knew that I would be like the canary in the coal mine in that there might be adverse side effects of the medication that had not been previously identified.
My external motivation was the opportunity to potentially contribute to the advancement of the care and treatment of people with Parkinson’s Disease (PD).
The PASADENA clinical trial was designed to study the usefulness of a monoclonal antibody in the treatment of PD. Many monoclonal antibodies are currently prescribed for other diseases (medications such as Humira, Prolia, Consentyx and Ketruda). They typically have a medical name that ends in “mab” for monoclonal antibody. This new drug, now named Prasinezumab, was developed to attack rogue alpha-synuclein cells that pathologically clump in persons with PD. If the drug succeeds as designed, it is hoped that it would substantially slow the ‘normal’ progression of the disease process. The drug was developed by a company called Prothena and is being studied in a joint venture collaboration with Roche.

This clinical trial was in two parts, year 1 and year 2. In year 1 the 300+ subjects were randomly assigned to either a placebo (control) group, low dose group or a high dose group. All assignments to group were blinded, so no one involved in the study knew the group to which any individual subject was assigned. In year 2 the subjects in the control group were randomly assigned to either a low dose group or high dose group. At that time the subjects in either high or low dose groups continued in their previously assigned group, so all subjects had ‘active’ drug infusions for the second year. Again, all group assignments were done blindly.

For both years all subjects received a 250 ml IV infusion once every 4 weeks (for me this took place in Boston, about 95 miles from our home in Western Massachusetts). Subject testing and examinations were conducted at these monthly visits as listed in the schedule in the Prothena presentation (see the tables in the two charts beginning on about slide 6 of the report from Prothena:)
http://ir.prothena.com/static-files/8e8d08ec-bea7-4abe-91c7-5e38a885618a.
These included the use of a common standardized assessment as the primary outcome, the sum of the scores of the first three parts of the Movement Disorder Society – Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). See the following link for details of this scale:

https://www.movementdisorders.org/MDS-Files1/PDFs/Rating-Scales/MDS-UPDRS_English_FINAL_Updated_August2019.pdf

The other assessments are detailed in the earlier Prothena link and include items such as the Timed Up and Go test, components of the Berg Balance assessment, gait evaluation and selected parts of a physical exam. Cognitive assessment (MoCA) and cardiac function via EKG were also included at intervals.
Data were also collected daily by use of a specially programmed cell phone and watch (see Prothena link, slide 8). The cell phone allowed monitoring of active tasks such as tremor, speech and balance. The study watch monitored activities such as gait and arm swing. Data from the phone and watch were automatically uploaded each day to the study sponsor.

An MRI scan, DaT SPECT scan, and a skin biopsy were completed as part of the initial screening, at the end of year 1 and at the end of year 2. Some subjects received a series of spinal taps (Note: to determine if antibodies had reached the brain), but this was optional, and I declined. Because of the challenges with COVID-19, I was not able to complete the third and final MRI or DaT SPECT scans; these have been tentatively scheduled for my 3-month follow up visit later this summer.

To be eligible to enroll in the study, subjects could not be taking a dopaminergic medication. I began the screening process in January 2018 and completed the two years of monthly infusions in April 2020. My PD symptoms worsened over the initial course of the study, and I was concerned that I might not be able and/or willing to stay in the study. At the 6 month mark I had classic features of untreated PD, including slow movements, rigidity, reduced arm swing, shuffling gait and diminished facial expressiveness. In addition, I was unable to exercise with the intensity, duration or vigor that I wanted to and felt that I needed to. After consulting with the research team and my movement disorder specialist, I started on a low dose Sinemet (25:100) three times a day. Gradually many of my symptoms improved, and I have subsequently continued with this level of medication.

At about the six month mark my wife and I began to travel to Tucson, typically every other month for a 3 week stay, and I participated in the 3 x week PWR gym HIIT class. In addition, I regularly ran and took a daily yoga class and worked 1:1 with a PWR gym physical therapist. My travel to Tucson stopped early February (2020), but I have continued with the running, on-line yoga and PWR gym HIIT class, now 2 x week.
I have heard that the study sponsor is currently planning to extend the Phase II study to an open label extension, available to interested Phase II participants following their completion of the trial. Details of this are not yet available. I intend to continue in the open label extension when it is available.

REFERENCES

Banks, W.A., S. A. Farr, J.E. Morley, K. Wolf, V. Geylis, and M. Steinitz (2007) Anti-Amyloid Beta Protein Antibody Passage across the Blood-Brain Barrier in the SAMP8 Mouse Model of Alzheimer's Disease: An Age-related Selective Uptake with Reversal of Learning Impairment. Exp Neurol. 2007 August; 206(2): 248–256.

Chatterjee, D. and J.H. Kordower (2019) Immunotherapy for Parkinson’s Disease: Current status and future directions. Neurobiology of Disease, 132: 104587.

Games, D. E. Valera, B. Spencer, E. Rockenstein, M. Mante, A. Adame, C. Patrick, K. Ubhi, S. Nuber, P. Sacayon, W. Zago, P. Seubert, R. Barbour, D. Schenk, E. Masliah (2014) Reducing C-Terminal-Truncated Alpha-Synuclein by Immunotherapy Attenuates Neurodegeneration and Propagation in Parkinson’s Disease-Like Models Journal of Neuroscience 34(28): 9441–9454

Games, D. P. Seubert, E. Rockenstein, C. Patrick, M. Trejo, K. Ubhi, B. Ettle, M. Ghassemiam, R. Barbour, D. Schenk, S. Nuber, E. Masliah (2013) Axonopathy in an α-Synuclein Transgenic Model of Lewy Body Disease Is Associated with Extensive Accumulation of C-Terminal-Truncated α-Synuclein. Journal of American Pathology 182 (3), 940-953 (2013)

Masliah, E., E. Rockenstein, M. Mante, L. Crews, B. Spencer, A. Adame, C. Patrick, M. Trejo, K. Ubhi, T. Rohn, S. Mueller-Steiner, P. Seubert, R. Barbour, L. McConlogue, M. Buttini, D. Games, D. Schenk (2011) Passive Immunization Reduces Behavioral and Neuropathological Deficits in an Alpha-Synuclein Transgenic Model of Lewy Body Disease PLoS ONE 6 (4), 1-17

Valera, E. and E. Masliah, (2013) Immunotherapy for neurodegenerative diseases: focus on α- Synucleinopathies, Pharmacol Ther. 138(3): 311–322.