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Parkinson’s Treatments Go After Genetic Targets

Series - AAT-AD/PD Focus Meeting 2018 - Advances in Alzheimer’s and Parkinson’s Therapies:

Current treatments for Parkinson’s disease target motor symptoms, and do nothing to halt progression or address other aspects of the disease. To get beyond this state of affairs, researchers are targeting the underlying disease pathology. They take guidance from genetic studies that have highlighted the major molecular players, such as α-synuclein, GBA, LRRK2, and tau. At the first Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting (AAT-AD/PD), held March 15–18 in Turin, Italy, speakers debated therapies aimed at all of these molecules. Several treatments are in or headed toward the clinic, and most could potentially work for dementia with Lewy bodies (DLB) as well. Researchers agreed the therapies—if they work—mark a sea change for synucleinopathy treatment.

  • Researchers are trying to develop disease-modifying therapies for PD.
  • Some targeting α-synuclein, GBA, and LRRK2 are in trials.
  • Some diabetes drugs are also in the mix.

“We are at a watershed moment for PD trials,” said Jesse Cedarbaum of Biogen. “If the drugs we’re developing work as we hope, they should address non-motor as well as motor symptoms.” Showing they do, however, will require new outcome measures to track change. “We have to rethink the clinical trial playbook,” Cedarbaum said.

Johan Luthman of Eisai stressed that PD is a multisystem disorder. “We need to get away from thinking of PD as a disease of dopamine cell loss, and instead think of it as a synucleinopathy,” he said. This shift in the PD field parallels the evolution in Alzheimer’s research, where scientists moved their focus from cholinergic deficits to the molecular pathogenesis of Aβ and tau.

Pharma Crosshairs Locked on α-Synuclein
In this conception of PD, preventing α-synuclein pathology is a primary approach. Several groups have designed antibodies they hope will arrest the spread of misfolded protein from cell to cell, with Biogen and Roche’s furthest along. Biogen did not present in Turin, but is recruiting for a Phase 2 trial of its antibody BIIB054, which targets aggregated α-synuclein. Biogen researchers will present Phase 1 data at the American Academy of Neurology annual meeting in Los Angeles later this month (May 2017 conference news). Meanwhile, Roche’s RG7935/PRX002, developed in partnership with Prothena, has also completed Phase 1 (May 2017 conference news) and did present in Turin. Based on pharmacokinetic data from this trial, the company is confident it is reaching the brain concentration necessary for target engagement, said Frank Boess of Roche.

Boess described the plan for the Phase 2 trial, dubbed PASADENA. A multicenter trial in the U.S., Austria, France, Germany, and Spain, it will enroll 300 people who have been diagnosed with PD within the last two years but are not yet taking dopaminergic medication. They will be between 40 and 80 years of age, and can be on a monoamine oxidase-B inhibitor such as rasagiline or selegiline.

Roche chose this population based on clinical data from the Parkinson’s Progression Markers Initiative and other studies that measured rates of change on the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). “We think at this point in disease there is the highest dynamic change in PD symptoms measured by the MDS-UPDRS, so we have a high chance of detecting a reduction in disease progression,” Boess said.

For the first year, one-third of the cohort will receive placebo and one-third a low dose of antibody, 1,500 mg. The remainder will take a high dose, which will vary by body weight—3,500 mg for people under 65 kg; 4,500 for those 65 kg or heavier. The high dose is roughly equivalent to the highest dose tested in Phase 1, 60 mg/kg, but transformed into flat doses to simplify administration, Boess said.

The primary outcome measure will be change on the MDS-UPDRS after one year; secondary measures include decline in DaT-SPECT imaging signal, which detects loss of dopaminergic synapses, the time before a participant starts symptomatic dopaminergic treatment, as well as other clinical measures, and drug pharmacokinetics. Researchers will monitor clinical features such as tremor, bradykinesia, gait, and dexterity using smartphones as an exploratory measure. Phase 1 data suggest this technology outperforms paper-and-pencil tests or clinician assessments (May 2017 conference news). 

After one year, placebo patients will cross over to one of the two active doses; patients and researchers will remain blinded to dose and the trial will run for an additional year. The FDA recommends this type of crossover design as a way to detect disease modification. The idea is that if the placebo group fails to catch up to the benefit seen with active treatment, then that suggests the treatment slows disease progression (Mar 2018 news). 

Vienna-based AFFiRiS AG completed Phase 1 testing of its Affitope PD03A vaccine, a peptide designed to generate antibodies against α-synuclein. In Turin, Werner Poewe of Innsbruck Medical University, Austria, who ran a clinical site, presented data showing that this one-year trial enrolled 36 early stage Parkinson’s patients who were on dopamine medication. They received four subcutaneous shots of either 15 mg or 75 mg antigen or placebo, at monthly intervals, and a booster at nine months. The trial met its safety and immunogenicity goals, Poewe said. Participants tolerated the injections, and no safety concerns or signs of encephalitis on MRI scans cropped up. The antigen provoked an immune response, with antibodies peaking one month after the third injection, and jumping again after the booster. The antibodies bound to α-synuclein in vitro, Poewe added. As shown also in Turin, a second vaccine, Affitope PD01A, performed similarly in a Phase 1 trial of 24 PD patients.

GBA Bears Blame for Some of the Worst Parkinson’s Cases
Other researchers are taking a different tack against PD pathology. Mutations in the glucocerebrosidase (GBA) gene occur in about 10 percent of Parkinson’s patients, and generally come with earlier onset, faster decline, and higher odds for psychosis or dementia. GBA accounts for a similar proportion of DLB cases. The mutations lower the activity of GBA’s protein product, the enzyme Gcase, by about two-thirds. This leads to a buildup of sphingolipids, in turn causing α-synuclein levels to rise. In a vicious cycle, aggregated α-synuclein may further depress Gcase activity, though the mechanism behind these relationships is unclear, Pablo Sardi of Sanofi Genzyme said.

Intriguingly, people with idiopathic PD and DLB also have weak Gcase activity, suggesting therapies that target this enzyme might help them, too (Gegg et al., 2012; Chiasserini et al., 2015). Low levels of Gcase activity correlate with earlier disease onset and worse non-motor symptoms. Sanofi has a GBA therapy in Phase 2, but did not present data in Turin (Dec 2016 conference news). 

Other researchers are developing the cough medicine Ambroxol as a GBA therapy. In Turin, Anthony Schapira of University College London explained that Ambroxol seems to act as a chaperone, binding mutant GBA in the endoplasmic reticulum and escorting it through the Golgi apparatus to the lysosome for degradation. In cellular and animal models of PD, the drug lowered α-synuclein levels, he said. Ambroxol is in Phase 2 PD trials in Canada and London, with a Phase 1 trial starting in Florida.

Schapira led the London trial, AIM-PD, which enrolled 12 GBA carriers and 10 people with idiopathic PD to look at safety and establish proof of principle. Participants took 1,200 mg/day of Ambroxol for six months. About 10 percent of the drug entered the central nervous system, based on the serum:CSF ratio. Blood levels of Gcase rose 30 percent in GBA carriers and 15 percent in those with idiopathic PD, suggesting the drug was hitting its target, Schapira said. Participants tolerated the treatment well, with no serious safety issues. In answer to an audience question, Schapira said that Ambroxol seems to help all GBA mutations tested so far. This pilot study collected efficacy data as an exploratory outcome measure, but Schapira did not discuss it in Turin. A larger Phase 2 study is enrolling. Nir Giladi of Tel Aviv University praised the target engagement signal in the AIM-PD study. “We are in a really exciting time. Our ultimate aim is to detect people at risk, treat early, and prevent symptoms altogether,” Giladi said in Turin.

Other Genetic Targets Moving Into Trials
LRRK2 variants, while less prevalent in PD than GBA mutations, drive up a carrier’s risk as much as 16-fold (Feb 2012 news). Because pathogenic variants increase LRRK2 activity, several groups are developing inhibitors. Denali Therapeutics in South San Francisco has two molecules in Phase 1, but did not present at AAT-AD/PD (press release). Other groups, including Pfizer, Merck, Glaxo-SmithKline, and Genentech, are beginning to test their own compounds.

No research groups are known to specifically target tau in PD, though mutations in the MAPT tau gene boost risk for PD (Charlesworth et al., 2012), and the gene takes second place in the Top Results list on PDGene. 

No tau, no α-synclein? Antibodies to oligomeric tau (right) prevented Lewy bodies (red) in mice that overexpress α-synuclein (left). Nuclei are stained blue. [Courtesy of Gerson et al., Molecular Neurodegeneration.]

Oligomers Interact? Antibodies to oligomeric tau (right) abolished oligomeric α-synuclein (green) in PD model mice (left). [Courtesy of Gerson et al., Molecular Neurodegeneration.]

In Turin, Rakez Kayed of the University of Texas Medical Branch, Galveston, said that all α-synuclein mouse models have tau pathology, and the two proteins have been found to interact whereby one triggers the other to form fibrils (Apr 2003 news; Jul 2013 news). Kayed treated seven-month-old A53T mice, which overexpress mutant human α-synuclein, with a single injection of tau oligomer-specific antibody (TOMA), and tested them two weeks later. The treatment lowered tau oligomers to almost wild-type levels, while rescuing nest-building behavior, novel object recognition, and gait (Gerson et al., 2018). “Tau immunotherapy helps β-synuclein mice,” Kayed concluded.

Diabetes drug for PD?
Some approaches lack a genetic basis. In fact, GWAS for PD, and also for Alzheimer’s disease, show no significant hits in diabetes genes. Still, the diabetes drug exenatide has been reported to halt motor decline in a small Phase 2 trial of 62 patients (Aug 2017 news). Exenatide is an analogue of glucagon-like peptide-1 (GLP-1), which stimulates the pancreas to release insulin. In a plenary session, Fabrizio Stocchi of IRCCS San Raffaele Pisana, Rome, noted that neurons express the GLP-1 receptor, particularly in the basal ganglia, and Christian Hölscher of Lancaster University, U.K., said that insulin-signaling falters in the PD brain. GLP-1 receptor agonists resensitize cells to insulin signaling. In animal models, exenatide protects dopaminergic neurons.

Hölscher wondered if other diabetes drugs might improve on GLP-1 receptor agonists. Some diabetes drugs target both GLP-1 and its cousin, glucose-dependent insulinotropic polypeptide (GIP). The scientists modified dual GLP-1/GIP receptor agonists to better enter the brain, and tested several in the MPTP mouse model of toxin-induced parkinsonism, as well as the OHDA rat model. The researchers gave the drug once daily for six days. Compared with the GLP-1 receptor agonist liraglutide, the dual agonists better protected synapses and dopaminergic neurons and reduced inflammation, Hölscher reported in Turin. The drugs restored levels of dopamine and growth factors such as insulin, BDNF, and GDNF, while reducing proinflammatory cytokines like TNF-a and IL-1b. The treatment improved the rodents’ gait, performance on the rotarod, and grip strength. Longer-lasting dual agonists worked best (Jalewa et al., 2017; Feng et al., 2018). The data suggest that dual agonists could be more effective than GLP-1 analogues alone, Hölscher said.

The most potent molecule, DA5, will go into the clinic for PD and indeed AD, said Hölscher, who holds patents on the compounds (Cao et al., 2018). He noted that these drugs do not directly affect glucose levels, and so can be taken by non-diabetics. In answer to audience questions, he said he believes the drugs act by restoring the apparatus that produces and releases dopamine.—Madolyn Bowman Rogers

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References

News Citations

  1. α-Synuclein Antibodies Enter Phase 2, Sans Biomarker
  2. Do Smartphones Collect Better Clinical Data Than Paper-and-Pencil Tests?
  3. FDA OKs Cognition as Sole Outcome Measure for Preclinical AD Trials
  4. Large Phase 2 Trial Starting Up in Genetic Parkinson’s Population
  5. More Than a LRRK: PD Field Thinks Big With Genetic Cohort
  6. Tau and α-synuclein at the Nexus of Alzheimer's and Parkinson's
  7. An Extra Strain on the Brain—α-Synuclein Seeds Tau Aggregation
  8. Diabetes Drug Improves Parkinson’s Motor Symptoms in Small Trial

Therapeutics Citations

  1. Exenatide
  2. Liraglutide

Paper Citations

  1. Gegg ME, Burke D, Heales SJ, Cooper JM, Hardy J, Wood NW, Schapira AH. Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Ann Neurol. 2012 Sep;72(3):455-63. PubMed.
  2. Chiasserini D, Paciotti S, Eusebi P, Persichetti E, Tasegian A, Kurzawa-Akanbi M, Chinnery PF, Morris CM, Calabresi P, Parnetti L, Beccari T. Selective loss of glucocerebrosidase activity in sporadic Parkinson's disease and dementia with Lewy bodies. Mol Neurodegener. 2015 Mar 27;10:15. PubMed.
  3. Charlesworth G, Gandhi S, Bras JM, Barker RA, Burn DJ, Chinnery PF, Gentleman SM, Guerreiro R, Hardy J, Holton JL, Lees A, Morrison K, Sheerin UM, Williams N, Morris H, Revesz T, Wood NW. Tau acts as an independent genetic risk factor in pathologically proven PD. Neurobiol Aging. 2012 Apr;33(4):838.e7-11. Epub 2012 Jan 4 PubMed.
  4. Gerson JE, Farmer KM, Henson N, Castillo-Carranza DL, Carretero Murillo M, Sengupta U, Barrett A, Kayed R. Tau oligomers mediate α-synuclein toxicity and can be targeted by immunotherapy. Mol Neurodegener. 2018 Mar 15;13(1):13. PubMed.
  5. Jalewa J, Sharma MK, Gengler S, Hölscher C. A novel GLP-1/GIP dual receptor agonist protects from 6-OHDA lesion in a rat model of Parkinson's disease. Neuropharmacology. 2017 May 1;117:238-248. Epub 2017 Feb 20 PubMed.
  6. Feng P, Zhang X, Li D, Ji C, Yuan Z, Wang R, Xue G, Li G, Hölscher C. Two novel dual GLP-1/GIP receptor agonists are neuroprotective in the MPTP mouse model of Parkinson's disease. Neuropharmacology. 2018 May 1;133:385-394. Epub 2018 Feb 17 PubMed.
  7. Cao Y, Hölscher C, Hu MM, Wang T, Zhao F, Bai Y, Zhang J, Wu MN, Qi JS. DA5-CH, a novel GLP-1/GIP dual agonist, effectively ameliorates the cognitive impairments and pathology in the APP/PS1 mouse model of Alzheimer's disease. Eur J Pharmacol. 2018 May 15;827:215-226. Epub 2018 Mar 15 PubMed.

Other Citations

  1. RG7935/PRX002

External Citations

  1. Phase 2
  2. Phase 1
  3. Phase 1
  4. Phase 2 
  5. Phase 1
  6. Phase 1
  7. Phase 2
  8. Canada
  9. London
  10. Phase 1
  11. Phase 2
  12. press release
  13. PDGene

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