Therapy focus – Novel Parkinson’s projects gather pace
Last week’s acquisition of Prexton by Lundbeck – along with recent data on Voyager’s gene therapy – raised hopes of a new era in Parkinson’s disease. Levodopa has been the mainstay of therapy for decades, but does not slow the progression of the disease and is associated with troublesome side effects.
While the projects in late-stage development mainly comprise different formulations of levodopa, the mid-stage pipeline is surprisingly crowded, with several new mechanisms in play (see table below). The compound that Lundbeck picked up with Prexton, foliglurax, is a case in point.
First in class
Foliglurax is a first-in-class mGluR4 regulator, and initial phase II data are expected in the first half of 2019, when it should become apparent whether Lundbeck made a good bet – the Danish company paid €100m ($123m) up front and is on the hook for up to €805m in milestones.
While current treatments aim to replace the dopamine lost in Parkinson’s or mimic its effects, foliglurax takes a different approach by increasing mGluR4 activity. This is thought to reduce activity in the brain pathway that inhibits movement, which is dominant in Parkinson’s disease, thereby restoring movement.
Because mGluR4 receptors are found in a part of the brain that is largely unaffected by Parkinson’s disease, it is hoped that foliglurax might escape one of the major problems seen with levodopa, namely that the drug becomes less effective over time as the brain degenerates.
Still, foliglurax does not promise a cure, and neither does Voyager’s gene therapy VY-AADC01. The latter is essentially designed to bolster levodopa’s efficacy by targeting the gene for the enzyme that converts levodopa to dopamine. Voyager reported promising but early data this month (Voyager still has a long way to go with Parkinson’s gene therapy, March 9, 2018).
VY-AADC01 could soon leapfrog the projects in the list below, since Voyager plans to start a phase II/III trial in the middle of this year. Results should be available in 2020, the company has told EP Vantage.
|Selected novel Parkinson's disease projects in phase II development|
|KM819||Kainos Medicine||FAS associated factor 1 inhibitor||NCT03022799||Jul 2017|
|SAGE-217||Sage Therapeutics||GABA A receptor regulator||NCT03000569||Sep 2017|
|Eltoprazine||Amarantus Bioscience||5-HT2C receptor antagonist; 5-HT1A receptor partial agonist; 5-HT1B receptor partial agonist||NCT02439125||Jun 2017|
|EPI-589||Sumitomo Dainippon Pharma||Redox cofactor||NCT02462603||Apr 2018|
|ITI-214||Intra-Cellular Therapies||PDE1 inhibitor||NCT03257046||May 2018|
|Ferriprox||Apotex||Iron chelator||Fairparkii, NCT02655315||Dec 2018|
|Foliglurax||Prexton (now Lundbeck)||mGluR4 regulator||Ambled, NCT03162874; Attuned, NCT03331848||Dec 2018; Feb 2019|
|CX-8998||Cavion||Calcium channel Cav3.2 blocker||NCT03436953||Jun 2019|
|Liraglutide (Victoza/Saxenda)||Novo Nordisk||GLP-1 receptor agonist||NCT02953665*||Jul 2019|
|CDNF Parkinson’s Project||Herantis Pharma||Cerebral dopamine neurotrophic factor||NCT03295786||Aug 2019|
|PRX002||Prothena||Alpha-synuclein accumulation antibody||Pasadena, NCT03100149||Mar 2020|
|GZ402671||Sanofi||Glucosylceramide synthase inhibitor||Moves-PD, NCT02906020||Mar 2021|
|BIIB054||Biogen||Alpha-synuclein accumulation antibody||Spark, NCT03318523||Apr 2021|
|GM608||Genervon Biopharmaceuticals||GM6 analogue||-||-|
|*Investigator-sponsored trial; Source: EvaluatePharma, Clinicaltrials.gov.|
As for other candidates that might soon go into late-stage trials, Sage Therapeutics has said that it will continue development of SAGE-217 in Parkinson’s. However, the company’s main focus for the project is depression.
South Korea’s Kainos Medicine aims to slow down the cell death seen in Parkinson’s with its novel FAF1 inhibitor KM819, but results from a phase II study that had been due to conclude last year have not yet materialised.
It is also unclear what has delayed Genervon’s GM608 – a phase IIa trial of that project in Parkinson’s finished in 2014, according to Clinicaltrials.gov; the company said in February that it was planning further phase II development in this indication.
The list above reveals that companies are trying many different ways of tackling Parkinson’s. An interesting approach comes from an investigator-sponsored study of Novo Nordisk’s diabetes/obesity drug liraglutide in the neurodegenerative disease.
It is thought that GLP-1 agonists like liraglutide could protect nerve cells from the damage seen in Parkinson’s as well as Alzheimer’s. Novo’s chief science officer, Mads Krogsgaard Thomsen, has previously told EP Vantage that the company’s next generation GLP-1, semaglutide, might be even more effective here because of its ability to cross the blood-brain barrier (Interview – Semaglutide holds the key to Novo’s success, October 3, 2017).
Another potentially disease-modifying approach could come from targeting alpha-synuclein. Because this protein clumps together to form Lewy bodies, which are hallmarks of Parkinson’s, it is hoped that this could slow disease progression.
Two companies have alpha-synuclein accumulation antibodies in phase II, according to EvaluatePharma: Biogen and Prothena. The latter recently got a boost from a deal with Celgene, though the Parkinson’s project looks unlikely to be covered by that agreement, which focused on tau, TDP-43 and a third, undisclosed target.
Other gene therapy approaches also hold promise. Oxford Biomedica has shifted away from the failed OXB-101/Prosavin, and plans to take a next-generation candidate, OXB-102, which it says has a more potent vector construct, into a phase I/II trial soon.
But this would not be a disease-modifying therapy; OXB-102 is designed to alter cells in the brain’s striatum to produce dopamine, so it would work in a similar way to levodopa. Still, the company believes that a single administration could produce an effect for years and not be affected by the gradual loss of efficacy seen with levodopa.
All of these projects are some way from the market. The next Parkinson’s therapy up for approval is Acorda Therapeutics’ inhaled levodopa Inbrija, which would not represent a huge shift away from current practice. Further behind are several candidates that, if successful, could help rejuvenate the stale Parkinson’s space.
This study has been updated to reflect the fact that the trial of liraglutide is investigator sponsored.