Parkinson's disease drug development: moving beyond L-DOPA

False colour MRI scan. 

It's been several years since I was engaged in licensing a treatment for Parkinson's disease (PD), but I recall being struck by the heavy reliance on just a handful of drugs and how empty the PD development pipeline then was. 

In this, the two hundredth year since James Parkinson first described the clinical features of the condition, it's good to see the emergence of potential new treatment options and signs of increasing big pharma involvement in PD drug development.

Like Alzheimer's disease, PD is age-related, with prevalence increasing some 20-fold between ages 60 and 80 in Europe and the US (the rise in PD cases is significantly greater in men than in women, prompting speculation on possible environmental causes of PD). And, again in common with Alzheimer's disease, the future burden of PD care constitutes a demographic time bomb.

The discovery that PD is associated with low levels of dopamine, a key neurotransmitter, resulted in the introduction of l-3,4-dihydroxyphenylanine ("L-DOPA"), a precursor of dopamine, in the 1960s. L-DOPA remains the cornerstone of PD treatment but at a price: long term use results in "off" effects, manifesting as stiff or slow movement and an increased frequency of involuntary movement ("dyskinesia"). Less commonly, L-DOPA can result in episodes of impulsive/compulsive behaviours. Additional medications are often needed to alleviate nausea and other L-DOPA side effects. The other main classes of PD drugs either substitute for dopamine or act by slowing down the biochemical breakdown of dopamine or of L-DOPA. 

PD drug development efforts have produced a variety of useful formulations and add-ons to increase and prolong the usefulness life of L-DOPA treatment but new therapies are needed to address the spectrum of PD non-motor and motor symptoms and to halt,  or at least substantially slow, disease progression. The first treatment to address L-DOPA associated dyskinesia (Gocovri™: Adamas Pharmaceuticals) has received FDA approval, although the FDA were less enthusiastic about accepting a marketing approval submission for Inbrija® (Acorda), an inhaled L-DOPA formulation that may reduce “off" symptoms.

As might be expected in a condition that manifests itself as a variety of not obviously connected symptoms, the pathophysiology of PD involves multiple mechanisms, a better understanding of which could lead to new classes of therapeutics.

The recently announced collaboration between AstraZeneca and Takeda is of note as it signals further big pharma involvement in PD drug development.  Efforts will be focused on a widely touted drug target, alpha-synuclein, a protein found in Lewy bodies- aggregates which accumulate in parts of the brain in PD patients and which may be central in spreading PD related  changes throughout the nervous system. AstraZeneca has also entered into an alliance with Berg Health to apply artificial intelligence to identify novel druggable targets in PD and other neurological diseases.

It's hoped that preventing  alpha-synuclein folding and aggregation might slow or even reverse PD progression. Trials of other anti-alpha-synuclein antibodies (developed by Prothena/Roche and Biogen) are underway, as is a study of a vaccine designed by an Austrian biotech, AffiRis AG, to elicit antibodies against alpha-synuclein. Neuropore, in partnership with UCB is evaluating an orally administered small molecule drug candidate, NPT200-11, which may prevent the accumulation of alpha-synuclein. Another alpha-synuclein modulating small molecule, PBT434 (Prana Biotechnology) has shown promise in animal studies.

The observation made around 40 years ago that certain synthetic opioids resulted in PD like symptoms in drug addicts suggested that mitochondrial defects might  be involved in PD, although no compelling case for a genetic basis for mitochondrial involvement  can be made. Edison Pharma believe that vatiquinone, an antioxidant which is in clinical development for inherited mitrochondrial disease may also have a role in PD treatment, with Phase II study results being announced last year.

Another candidate with a novel mode of action is Foliglurax (Prexton Therapeutics), which acts by modulating the metabotropic glutamate receptor 4 (mGluR4) to restore the imbalance in neurotransmitters believed to cause PD dyskinesia.  A recently published study in which exenatide, an injected synthetic peptide drug used in the treatment of Type 2 diabetes, brought about improvements in PD patients adds weight to the hypothesis that reduced insulin signalling in the brain plays a role in PD and other neurodegenerative conditions.

PD drug development has a historically high failure rate but, between new targets and improved clinical study design, perhaps aided by validated PD biomarkers, it’s reasonable to expect an expansion of PD treatment options over the next ten years, with a realistic prospect of being able to slow disease progression in at least some individuals.

Photo credit: NIH Image Bank

Athauda D et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet 2017; published online 3rd August 2017. http://dx.doi.org/10.1016/S0140-6736(17)31585-4.

Minutes after publishing this, I noticed a post on Derek Lowe's excellent "In the Pipeline" blog concerning a Norwegian study in which a lower risk of developing PD rates was associated with the use of salbutamol, a common asthma medication. 

A New Piece of the Parkinson’s Puzzle. Derek Lowe, "In the Pipeline" online 5th September 2017.
http://tinyurl.com/y9kfdnt2

While not focused on PD, there's a highly readable overview by Chris Morrison in Chemical and Engineering News of how genetic analysis has the potential to define and target subgroups within the major neurodegenerative diseases, leading to mutation-directed therapy and smaller clinical study groups. 

A path to the brain’s secrets. Chris Morrison, C and EN online 4th September 2017.
http://tinyurl.com/ybqznq34