Background

PD01A is an active vaccine to α-synuclein. The immunogen is an eight amino acid peptide that mimics an epitope in the C-terminal region of human α-synuclein, but with a different amino acid sequence. The peptide is conjugated to the carrier protein keyhole limpet hemocyanin and adsorbed to aluminum hydroxide adjuvant. The vaccine is designed to stimulate B cell antibody responses, but bypass auto-reactive T cell mobilization, which can elicit harmful neuroinflammatory responses.

Antibodies to α-synuclein have been shown to prevent pathogenic protein spread and promote clearance of aggregates in animal models (Bae et al., 2012; Masliah et al., 2011). AFFiRiS was developing PD01A and a related vaccine, PD03A, for the synucleinopathies Parkinson’s disease and multiple system atrophy (MSA).

The PD01A immunogen was selected by screening a library of synthetic peptides with a monoclonal antibody to α-synuclein oligomers. When used to vaccinate mice, the PD01A peptide induced antibodies that recognized α-synuclein aggregates preferentially over monomers, and did not react with β-synuclein (Mandler et al., 2014). Immunization of two mouse lines overexpressing human α-synuclein lowered brain levels of aggregated α-synuclein, reduced neurodegeneration, and improved memory and motor behaviors. Immunization likewise decreased neurodegeneration and demyelination in a mouse model of MSA (Mandler et al., 2015). In an APP/α-synuclein double-transgenic mouse, dual immunization with PD01A and an Aβ vaccine had additive benefits on pathology and behavior (Mandler et al., 2019).

Findings

In February 2012, AFFiRiS began a Phase 1 safety and tolerability study of PD01A. The single-site trial in Vienna enrolled 32 people between 45 and 65 years old with early stage idiopathic Parkinson’s disease on stable medication. Twenty-four participants received four doses of 15 or 75 μg PD01A spaced four weeks apart and were observed for one year; eight people served as an untreated comparison group. The company reported favorable findings on safety and immunogenicity (Mar 2015 conference news), and the study was extended to include an additional nine months follow-up. In a second extension, the 22 remaining participants were rerandomized to a single booster of 15 or 75 μg, with 24 weeks follow-up. In a final extension, the 21 remaining participants received a second booster of 75 μg, and were followed for one year. The primary endpoints throughout were adverse events and trial withdrawal. Secondary endpoints included antibody titers, measures of motor and nonmotor symptoms, and CSF levels of α-synuclein, Aβ, and tau.

The trial finished in 2017, and results are published (Volc et al., 2020). The vaccine was well-tolerated, with 21 of 24 participants completing the 3.5-year study. The most common adverse event was transient, local-injection-site reaction. A few percent of participants reported fatigue, headache, and nausea. No one withdrew due to adverse events. MRI revealed no evidence of brain inflammation. Both priming doses produced significant IgG titers in 23 of 24 participants. Antibody levels returned to baseline two years after the first dose, and rapidly increased to higher than the original titers after booster immunizations. Antibodies preferentially bound to α-synuclein oligomers over native α-synuclein, and could be detected in CSF of high responders. A post hoc analysis found a 51 percent reduction in CSF α-synuclein oligomers after four 75 μg priming doses. Total α-synuclein, Aβ, total tau, and phosphoTau181 did not change.

From November 2014 to November 2016, AFFiRiS conducted a Phase 1 study with its second candidate, PD03A, in 36 people with Parkinson’s disease. Participants received four priming vaccinations with 15 μg, 75 μg, or aluminum oxyhydroxide adjuvant four weeks apart, plus a booster at nine months. According to presentation at the AAT-AD/PD Focus Meeting 2018, the vaccine was safe and well-tolerated, and produced a dose-dependent IgG response to α-synuclein (Apr 2018 conference news). Full trial results have been published, reporting that PD03A achieved lower antibody titers than previously observed with PD01A (Poewe et al., 2021).

Beginning in April 2017, the company tested both PD01A and PD03A in 30 people with MSA. The Phase 1 study, at two sites in France, enrolled patients from 30 to 75 years old, in the early stage of disease. Thirty received four subcutaneous injections of 75 μg PD01A or PD03A, once every four weeks, and one booster at nine months; six received the same schedule of adjuvant only. Primary outcome was number of withdrawals and adverse events, plus clinical lab and MRI safety assessments. Secondary measures included antibody titers and change in motor and non-motor symptoms one year after the first vaccination. According to published trial results, the safety profile matched that seen in previous trials for Parkinson’s disease, with injection-site reactions being the most common adverse event (Meissner et al., 2020). Three deaths in the trial were deemed unrelated to immunization. PD01A vaccination generated α-synuclein-reactive IgG in 89 percent of treated patients. The PD03A responder rate was 58 percent, and titers were lower than PD01A.

An additional Phase 1 study was registered in 2016 to be run in Tübingen, Germany, but withdrawn before enrollment began. The study was to have evaluated PD01A versus placebo in 30 PD patients with GBA mutations.

In January 2020, AFFiRiS announced it intended to begin a Phase 2 of PD01A for Parkinson’s disease in late 2020 (press release); no trial was registered.   

In July 2021, AC Immune announced it had acquired rights to the PD01 (press release).

In July 2023, a Phase 2 trial began testing an optimized formulation of the vaccine, called ACI-7104.056. The trial's adaptive design will begin enrolling up to three cohorts of 16 early-stage Parkinson’s disease patients, to be randomized 3:1 to vaccine or placebo for 74 weeks. One of the cohorts may be expanded to up to 150 subjects overall, with a randomization of 2:1 active treatment:placebo. Primary outcomes include adverse events, changes on MRI, and levels of α-synuclein antibodies. Secondary outcomes are changes in α-synuclein related biomarkers, dopamine transporter PET scans, and motor and non-motor symptoms. The trial, in Germany, Spain, and the United Kingdom, is expected to finish in January 2028.

In a January 2024 business update, the company reported that enrollment in the first cohort was complete, and the second cohort had started (press release). No safety concerns had emerged.

For details on PD01A and PD03A trials, see clinicaltrials.gov.

For ACI-7104.056, see clinicaltrials.gov.