Name: Affitope PD01A
Therapy Type: Immunotherapy (active) (timeline)
Target Type: alpha-synuclein
Condition(s): Parkinson's Disease, Multiple System Atrophy
U.S. FDA Status: Parkinson's Disease (Phase 2), Multiple System Atrophy (Phase 1)
Company: AFFiRiS AG
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 absorbed 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 is 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).
In Feb 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 December 2014 to August 2016, AFFiRiS conducted a Phase 1 study with their 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 (April 2018 conference news).
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 9 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 intends to begin a Phase 2 of PD01A for Parkinson’s disease in late 2020 (press release); no trial was registered as of October.
For details on PD01A trials, see clinicaltrials.gov.
Last Updated: 08 Oct 2020
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