α-Synuclein Antibody Misses Primary, May Have Signal on Secondaries

Series - AAT-AD/PD™ 2020 Conference: Advances in Alzheimer's and Parkinson's Therapies:

Roche and Prothena today announced topline results from the first half of their Phase 2 trial of the α-synuclein antibody prasinezumab. Results were negative on the MDS-UPDRS, the primary outcome measure, but the company said it saw signals of efficacy on multiple secondary and exploratory clinical endpoints. The findings were included in Roche’s quarterly earnings report, and no further details were available. Roche continues to analyze the data, and is discussing next steps with health authorities.

  • Topline results from prasinezumab were negative on primary, the MDS-UPDRS.
  • The trial collected a wealth of secondary outcome data, some of which is reportedly positive.
  • Another α-synuclein antibody, from AC Immune, will enter clinical studies.

Meanwhile, at the second biannual Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting (AAT-AD/PD), held virtually April 2 to 5, researchers from Roche presented baseline data from this trial, as well as data suggesting that exploratory digital measures collected by smartphones may indeed be useful. Immunotherapy approaches remain popular, with AC Immune researchers at the conference describing an antibody candidate about to enter the clinic.

Because misfolded α-synuclein is believed to spread from cell to cell, numerous groups are targeting this extracellular form of the normally intraneuronal protein with antibodies. Biogen’s antibody BIIB054 is in Phase 2 but the company did not present at AAT-AD/PD (May 2018 conference news). Other candidates, such as AbbVie’s ABBV-0805 and AstraZeneca’s MEDI1341, remain in Phase 1.

Roche/Prothena’s prasinezumab is the furthest along clinically. It selectively recognizes aggregated α-synuclein over monomeric forms. Phase 1 data showed that it reached the brain (May 2017 conference news), so Roche launched the Phase 2 PASADENA study in 2017. This study consists of a one-year, placebo-controlled trial, followed by a one-year blinded extension where placebo participants will cross over to one of the two active doses (Apr 2018 conference news). 

At AAT-AD/PD, Roche’s Gennaro Pagano reported baseline data from this trial. It enrolled 316 participants, two-thirds of them men, whose mean age was 60. They were fairly newly diagnosed with PD, having had the disease for an average of 10 months at baseline. A quarter were at Hoehn and Yahr stage 1, meaning they were mildly rigid, slow, or had a one-sided tremor. The remaining three-fourths were at stage 2, with symptoms on both sides of the body but no balance problems yet. Their mean score on the MDS-UPDRS was 31.4, indicative of early disease. PD patients average 68.4 on this scale (Goetz et al., 2008). The study is conducted at 64 sites in the U.S., France, Spain, Germany, and Austria.

This trial was designed using the Parkinson’s Progression Markers Initiative cohort as a reference. PPMI participants are also at an early stage, enrolling within three to six months of their diagnoses. However, PPMI participants are not allowed to be on monoamine oxidase-B inhibitors such as rasagiline or selegiline, while PASADENA participants are. The medication difference did not seem to affect the characteristics of this cohort, Pagano said. Adjusting for the difference in disease duration between the PPMI and PASADENA cohorts, the severity of motor symptoms was similar between the two groups, suggesting their disease progression rates may be similar too, Pagano said. He believes including patients on MAO-B therapy was the right call.

Roche’s previous ScarletRoAD trial of gantenerumab had disallowed concomitant AD therapies. This led to disproportionate dropouts in the placebo group, as people who noticed they were declining left the trial to go on those medications (Nov 2015 conference news). 

The PASADENA cohort did differ from PPMI in other regards, with slightly less severe non-motor symptoms and a smaller dopaminergic deficit on DaT-SPECT imaging. Those aspects of disease might progress differently than predicted from the PPMI data, Pagano acknowledged. Overall, he concluded, “The PASADENA population can be considered representative of a wider PD population, and therefore suitable for testing the potential beneficial effects of drugs acting on disease progression.”

The trial’s primary outcome measure was change on the MDS-UPDRS total score, which evaluates motor and non-motor aspects of PD, over the first year of the study. Pagano said the researchers refined secondary outcome measures for this trial to take a more granular look at disease progression. They will separately evaluate scores from the MDS-UPDRS Part 1, which tracks non-motor symptoms; Part II, which measures movement-based activities of daily living; and Part III, which measures motor symptoms. They will also compare the time to worsening on each of these subscales, as well as take other clinical and cognitive measures such as the Clinical Global Impression Improvement, the Patient Global Impression of Change, the Schwab and England Activities of Daily Living Scale, and the Montreal Cognitive Assessment. The MDS-UPDRS were evaluated every eight weeks throughout the first year of the study, the other measures every six months. The study was designed to have 80 percent power to detect a 37.5 percent slowing of progression on the MDS-UPDRS over one year.

The topline results reported today apply to the placebo-controlled portion of the trial. The crossover portion is still running, although Prothena noted that some assessments have been missed due to the coronavirus pandemic.

The trial also includes exploratory digital measures of motor and non-motor abilities, evaluated by smartphone and a wearable wrist device (May 2017 conference news). Gait and mobility analyses are passively recorded. In addition, participants take tests of hand dexterity, speech, and balance, alternating tests on different days. Compliance tends to be a problem with mobile phone-based tests that require consistency, but Pagano said that preliminary data indicates that most participants are completing these tests five or six days every week.

Toward validation of those new tests, Roche’s Alessandra Thomann at AAT-AD/PD reported that digital measures of hand movement correlated with participants’ own assessments of their overall health and ability to function, and gait measures correlated with their ratings of their own mobility and discomfort. Roche’s Florian Lipsmeier reported that gait and arm movement measures dovetailed with MDS-UPDRS scores for slowness, rigidity, and activities of daily living, again suggesting these will be useful markers of progression.

A different therapeutic α-synuclein antibody is coming out of the labs at AC Immune in Lausanne, Switzerland. At AAT-AD/PD, AC Immune’s Elpida Tsika described their SupraAntigen method, which conjugates an antigen to a liposome that also contains adjuvants, to develop several antibodies that recognize different epitopes of α-synuclein. The researchers screened them to find the one with the best properties to take forward. The lead candidates were selective for aggregated over monomeric α-synuclein in dot blots, and had a 20 times slower dissociation rate from fibrils than monomers in surface plasmon resonance assays, indicating high affinity. In sections from postmortem PD brains, these antibodies labeled Lewy bodies.

Can they hold back pathology? When mixed with monomeric α-synuclein and aggregated seeds, the lead antibodies slowed in vitro fibril formation by 50 percent, from 30 to 45 hours. In a cellular assay, the antibodies dose-dependently lowered the amount of aggregates taken up by mouse primary cortical neurons, Tsika reported.

The researchers tested the three top candidates in M83 hemizygous transgenic mice expressing human A53T α-synuclein. They injected preformed α-synuclein fibrils into the anterior olfactory nuclei of 8-week-old mice, then treated them with 30 mg/kg antibody by intraperitoneal injection for four months. Antibodies ACI-mAb-1 and ACI-mAb-5 had the strongest effect, halving α-synuclein aggregates in contralateral brainstem and piriform cortex, and increasing body weight in treated animals. ACI-mAb-10 had little effect on pathology or body weight, but did preserve neurons in ipsilateral piriform cortex, as did ACI-mAb-1.

Tsika said a lead candidate was humanized last year and is in preclinical development now, but did not say which one was picked.—Madolyn Bowman Rogers

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References

Therapeutics Citations

  1. Prasinezumab
  2. Cinpanemab
  3. Exidavnemab
  4. TAK-341

News Citations

  1. New Alzheimer’s and Parkinson’s Immunotherapy Data at AAN
  2. α-Synuclein Antibodies Enter Phase 2, Sans Biomarker
  3. Parkinson’s Treatments Go After Genetic Targets
  4. Gantenerumab, Aducanumab: Bobbing Up and Down While Navigating Currents of Trial Design
  5. Do Smartphones Collect Better Clinical Data Than Paper-and-Pencil Tests?

Paper Citations

  1. Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stern MB, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, van Hilten JJ, LaPelle N, Movement Disorder Society UPDRS Revision Task Force. Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008 Nov 15;23(15):2129-70. PubMed.

External Citations

  1. announced 
  2. PASADENA 
  3. Parkinson’s Progression Markers Initiative

Further Reading

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