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α-Synuclein Antibodies Enter Phase 2, Sans Biomarker

Series - AD/PD 2017 Draws Record Number of Scientists To Vienna:

In the search for ways to slow down the progression of Parkinson’s disease, researchers currently have α-synuclein in their crosshairs. A handful of approaches are in development, and immunotherapy strategies are now advancing through clinical trials. At the 13th International Conference on Alzheimer’s and Parkinson’s Diseases, held March 29 to April 2 in Vienna, speakers from Prothena and Biogen presented Phase 1 data on their respective α-synuclein antibodies. Prothena discussed plans for Phase 2, including smartphone monitoring to collect more detailed clinical data (see related AD/PD story). At the same time, researchers bemoaned the continued absence of good biomarkers to track disease progression and show efficacy of their drugs. What they really want is a PET tracer that detects pathological forms of the protein in living brain. Motivated by a large prize, scientists are working feverishly to find tracers, and in Vienna, Andreas Muhs of AC Immune, Lausanne, Switzerland, showed preclinical data on a candidate that selectively binds aggregated α-synuclein and appears to have suitable pharmacokinetics in rodents.

Academic and pharmaceutical researchers at AD/PD said they feel more hopeful than ever for meaningful progress on this disease. “The science has gotten more sophisticated, and we’re taking good bets in the clinical space,” noted Gene Kinney, who leads Prothena. At the same time, Kinney cautioned that many unknowns in these new types of trials make the way forward unclear.

α-Synuclein Specific.

A candidate α-synuclein PET tracer (blue) binds to aggregated α-synuclein (red; overlay appears pink), but not amyloid plaques (green) in PD brain sections. [Courtesy of AC Immune.]

One of these unknowns is whether lowering α-synuclein levels will actually slow disease progression, said Werner Poewe of Innsbruck Medical University, Austria, in a plenary talk. At the time PD is diagnosed, half of the neurons in the substantia nigra have already died, he noted. Eliezer Masliah, who heads the National Institute on Aging’s Division of Neuroscience, urged the PD field to learn from AD trials. “Don’t put antibodies into late-stage patients,” he advised. 

There is broad consensus that preventative trials would be ideal. At the same time, many scientists believe that antibodies do hold potential to help symptomatic patients if they stop the transfer of pathological α-synuclein from cell to cell, thus halting its spread through the brain (see Jun 2014 news). Kinney noted that those antibodies that best prevent transfer in cell culture are the ones with the strongest protective effects in animal models. Even so, Prothena researchers have found that antibodies can mop up intracellular pathology as well, Kinney said. Serena Hung of Biogen, who leads her company’s PD program, said that she sees the same phenomenon in her studies, as well.

First α-Synuclein Antibodies Head to Phase 2
Both the Prothena and Biogen α-synuclein antibody programs are at a similar stage, completing safety and dose-finding studies. In Vienna, Joseph Jankovic of Baylor College of Medicine, Houston, described findings with Prothena’s antibody PRX002. It binds aggregated forms of α-synuclein 400 times more strongly than monomeric forms, Jankovic noted. In mice, it lowers pathology, protects synapses, and improves motor abilities. PRX002 previously completed a Phase 1 study in healthy volunteers, where it appeared safe and suppressed α-synuclein levels in the blood (Mar 2015 conference news; Schenk et al., 2017). The antibody is now being developed in collaboration with F. Hoffmann-La Roche in Basel, Switzerland.

In Vienna, Jankovic reported on the results of a Phase 1b trial in PD patients. He ran a site for this trial, which enrolled 80 people from 40 to 80 years old, predominantly white men, who had mild to moderate Parkinson’s. Each received antibody by IV once a month for three months at one of six doses: 0.3, 1, 3, 10, 30, or 60 mg/kg; a third of the cohort received placebo. After dosing, participants were followed for an additional 12 weeks.

The antibody appeared safe, Jankovic said. Participants did not make anti-drug antibodies. There were no serious adverse events, though some people reported skin reactions such as rash at the infusion site, and others had gastrointestinal complaints, headaches, or peripheral edema. Participants showed no improvement whatsoever on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), though that was not expected in this relatively short study, Jankovic said.

The pharmacokinetic profile was largely typical for an antibody, although the half-life was on the short side at 14 days. As with other antibodies, only 0.3 percent of the amount in blood made it into CSF. This CSF/serum ratio was the same for all dose groups at week nine. Unbound α-synuclein in serum dropped by as much as 97 percent at the highest antibody dose, indicating target engagement in the periphery. Antibody levels rose in CSF in accordance with dose, but the amount of monomeric α-synuclein in CSF did not change. This was expected, since PRX002 targets primarily aggregates, Jankovic noted. The scientists do not have an assay to measure the concentration of α-syn aggregates in CSF before and after treatment.

Based on these findings, Prothena and Roche will begin a Phase 2, year-long efficacy study in 300 PD patients this year, with the primary outcome being change on the MDS-UPDRS.

Meanwhile, Biogen’s antibody BIIB054 is not far behind. Like PRX002, this human monoclonal antibody binds pathological, aggregated α-synuclein while sparing physiological forms. It was not clear whether physiological means the monomer or a postulated tetramer, and Biogen researchers could not be reached for comment. In Vienna, Andreas Weihofen of Biogen, Cambridge, Massachusetts, presented preclinical findings. In cell culture, BIIB054 reduced spreading of aggregated α-synuclein between neurons, and in mice injected with α-synuclein fibrils, BIIB054 slowed down pathology and improved motor function, Weihofen said.

In 2015, Biogen started a Phase 1 single ascending dose study in 48 healthy people between age 40 and 65. At two U.S. sites, volunteers received infusions of either 1, 5, 15, 45, 90, or a whopping 135 mg/kg, reported Biogen’s Miroslaw Brys in Vienna. Participants underwent three MRI scans, at baseline, day three, and week four. They donated CSF samples at baseline, eight hours, 24 hours, and week three. Researchers followed participants for 16 weeks after dosing, doing clinical assessments and electrocardiograms in search of adverse effects.

Doses up to 90 mg/kg were well-tolerated, with similar adverse events on placebo and drug, Brys said. In the 135 mg/kg cohort—which translates to 9.4 grams in a person weighing 70 kg, or 154 pounds—one participant developed asymptomatic ischemia in the right parietal lobe; this dose will not be used further. Some participants complained of headache, dizziness, or pain related to the infusion, and one person developed a skin rash at the infusion site.

The pharmacokinetic profile was as expected, with a half-life of 28 days and a CSF/serum ratio of 0.2 percent at all doses. The maximum concentration in blood was proportional to the antibody dose given. The researchers are still analyzing what happens to plasma α-synuclein, Brys noted. This trial is ongoing, aiming to enroll 66 people, but based on the preliminary data, the researchers are already planning to take BIIB054 into Phase 2, Brys said.

Wanted, Oh So Badly: PET Tracer for α-Synuclein
One thing everyone in the field readily agrees on is the urgent need for a better biomarker of α-synuclein for trials. A PET tracer would allow researchers to track both accumulation of the aggregated protein in the brain at preclinical stages, as well as reduction due to anti-α-synuclein treatment. “A PET marker would be game-changing,” said Walter Koroshetz, who runs the National Institute of Neurological Disorders and Stroke (NINDS). Scientists have been working on this goal for years, with little success. To hurry things along, the Michael J. Fox Foundation has offered a $2 million prize to the first group to develop one.

In Vienna, Muhs debuted a candidate, saying that AC Immune has tested a chemical library to find compounds specific for aggregated α-synuclein. They found two compounds that fit the bill. They bind recombinant α-synuclein oligomers with 2-6 nanomolar affinity in vitro. In unfixed human postmortem brains from PD patients, both compounds lit up Lewy bodies and neurites. They also bound to α-synuclein aggregates in brain sections from people who had multiple system atrophy (MSA) type C.

One particular challenge for an α-synuclein tracer is that it be specific for the protein over aggregated Aβ, which also forms β-sheets and often occurs along with Lewy bodies in PD, dementia with Lewy bodies (DLB), and AD. At AD/PD, Muhs showed data to demonstrate that their candidate compounds do not bind Aβ. In late-stage AD and PD brains that contained Aβ plaques, the new compounds did decorate the fringes of plaques—but this was because α-synuclein also clustered around these structures. Triple staining confirmed that the compounds were binding only to bona fide α-synuclein structures, not Aβ, Muhs told the audience (see image above). The researchers also verified by way of postmortem tissue autoradiography studies that their compounds did not compete with amyloid tracers for binding to amyloid plaques in the amygdalas of AD patients.

In pharmacokinetic tests, one of the two compounds, dubbed “H,” had good brain uptake and fast washout, while the other had low brain uptake. Muhs said they will take H forward, with the next step being to radiolabel it. In answer to audience questions, he said it was not yet clear if other body tissues besides brain take up the compound, or how it might be cleared from brain. AC Immune is developing the compound in collaboration with Biogen.—Madolyn Bowman Rogers

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References

News Citations

  1. Do Smartphones Collect Better Clinical Data Than Paper-and-Pencil Tests?
  2. Synuclein Snatch: Antibodies Snag Protein En Route to Next Neuron
  3. Antibody Against α-Synuclein Looks Safe In Phase 1

Therapeutics Citations

  1. Prasinezumab

Paper Citations

  1. Schenk DB, Koller M, Ness DK, Griffith SG, Grundman M, Zago W, Soto J, Atiee G, Ostrowitzki S, Kinney GG. First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers. Mov Disord. 2017 Feb;32(2):211-218. Epub 2016 Nov 25 PubMed.

External Citations

  1. Phase 1
  2. Phase 1b
  3. Phase 2
  4. Phase 1
  5. $2 million prize

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