Parkinson's disease: the struggle to control symptoms

Parkinson's disease: the struggle to control symptoms

After Alzheimer's, Parkinson's disease (PD) is the most common neurodegenerative disorder, affecting more than 7 million people globally. More importantly, the number of people affected by PD is expected to at least double by 2030. Currently, the economic impact of PD in the US alone is estimated at more than $14.4 billion, with indirect costs estimated to be at least $6 billion. Given a potential doubling of affected populations over the next few decades, the costs of the disease are expected to grow rapidly. Though there is no cure for PD, a number of drug treatments can help relieve symptoms. There are currently some 16 treatments approved, mostly combinations of levodopa, plus more than a dozen or so other drugs in Phase II or III trials.

First line medication

Levodopa and dopamine agonists are the first line of defence in PD. Levodopa remains the most effective medication available for treating motor complications such as tremor (dyskinesia). Drugs such as Sinemet (levodopa plus carbidopa), from Merck, have been around since the 1970s and are now generic. Carbidopa inhibits peripheral metabolism of levodopa, maximising the amount reaching the brain. In Madopar (levodopa plus benserazide), from Roche, benserazide acts in a similar way to carbidopa. However in some instances other medication may be initiated first to avoid serious dyskinesia. This includes monoamine oxidase-B inhibitors (MAOBIs) such as Azilect (rasagiline mesylate), from Teva/Lundbeck which was first approved a decade ago. A newer MAOBI is Xadago (safinamide), from Zambon SpA, which was re-filed in the US in 2014 and approved in the EU in 2015.

New delivery modes

Another approach to reducing dyskinesia has been to alter delivery mode, with the aim of reducing the constant high level of drug in the body, which usually results from conventional oral treatment. For example, Nurelin (ADS-5102, amantadine HCl extended release), from Adamas Pharmaceuticals, is currently in Phase II/III trials. The drug increases dopamine release, and blocks dopamine reuptake. This formulation is designed for once-nightly administration, and is expected to result in high plasma concentrations during the daytime hours when dyskinesia can be troublesome, and low plasma concentrations overnight. Trials show it can be effective, despite a 2003 Cochrane review suggesting there is no strong evidence that conventional amantadine formulations are effective. Other extended release formulations are Requip XL (ropinirole extended release), from GlaxoSmithKline, which was approved in 2008 and is now generic, along with Rytary (carbidopa-levodopa extended release), from Impax Labs. This was approved in the US in 2015, while it is currently in Phase III trials in the EU. As with Requip XL, Rytary is intended to maintain lower concentrations of levodopa for a longer duration than immediate release treatments.

Transdermal delivery is also being investigated as a way to modulate dosage. Neupro uses a transdermal patch, with dopamine agonist rotigotine. Phase III clinical trial results showed that this transdermal drug delivery was able to significantly increase the amount of time for which the treatment is effective without troublesome dyskinesia and gastrointestinal side-effects. Developed by Schwarz/UCB, it was approved in the US in 2012.

Other companies have developed alternatives to transdermal patch delivery. Duopa/Duodopa (levodopa plus carbidopa gel), from AbbVie, was approved by the EU in 2009 and in the US in 2015. Duodopa is used for the treatment of motor fluctuations for people with advanced Parkinson's disease and provides patients with the same active ingredients as oral carbidopa and levodopa immediate release but is administered using a small, portable infusion pump that delivers the combination directly into the small intestine, so bypassing the stomach. Compared to conventional oral levodopa, Duodopa provides smoother levodopa plasma levels, helping to increase the effective period.

There is also the inhalation route for levodopa. Civitas Therapeutics and Acorda are in Phase III trials with CVT 301, which delivers a precise dose of levodopa to the lung for rapid and predictable absorption. The system is self-administered, and results in Phase II have been promising. Though current treatments can boost dopamine production temporarily, the main challenge is that the cells that produce the chemical continue to degenerate until conventional treatments no longer work.

One long-term solution is to stimulate a different set of cells to produce dopamine. Gene therapy treatment aims to do just that. For example, ProSavin, from Oxford Biomedica, is in early trials. Results are promising, with benefits being sustained over several years. Other PD gene therapies include VY-AADC01, from Genzyme/Sanofi, and CERE 120 from Ceregene, which are also both in early trials.

Direct electrical stimulation

Research in the 1980s showed that electrical neurostimulation – so called ‘deep brain stimulation’ (DBS) – could tackle motor control problems in Parkinson’s patients, though it wasn’t a cure. DBS for the treatment of PD symptoms was first granted approval in 2002. Currently around a dozen treatments based on electrical neurostimulation are approved or in trials, but many more are likely to follow: the global market for DBS in Parkinson’s disease reached $1.8 billion in 2013 and is predicted to reach $3.2 billion by 2020.

Probably the current market leader is Medtronic’s Activa series – which is EU- and US-approved. These small neurostimulator devices are implanted with leads and electrodes into the brain to treat symptoms of PD. The different models have different characteristics – for example, the Activa PC+S, so far approved only in the EU, pairs traditional DBS with sensing technology allowing it to administer standard therapy while sensing and recording electrical activity in key areas of the brain. And with more than 90,000 patients worldwide already using Medtronic DBS systems, the company earns around $2 billion annually from its neuromodulation devices, making it the largest player in the market.

Medtronic also owns Sapiens, which is developing the Sure Stim 1 DBS, an innovative high-resolution implant with the capacity to steer electrical pulses away from areas of the brain that can produce undesirable side-effects. It is currently in early trials.

The only other manufacturer with a DBS system approved for the US market is St Jude. Its Brio Neurostimulation System was approved in the EU in 2009, and in the US in 2015. Brio is one of the smallest devices, with amongst the longest life battery supply. St Jude also makes the EU-approved Libra DBS device. St Jude currently makes around $500 million annually from its electrical stimulation products.

Boston Scientific is another major competitor. Its Vercise DBS device was approved for PD in the EU in 2012, but it remains under investigation for use in the US. Results from the CUSTOM-DBS study suggest that since the Vercise System is designed to generate stimulation pulses at shorter width settings, it can provide effective treatment with fewer unwelcome side effects. Challenges for the technology are the high cost of implantation, along with the risk of side-effects such as infection at site of implant, as the implantation is a surgical process. There is also evidence for intracranial bleeding, which can lead to stroke, paralysis or death.

In the longer term, some of these issues could be solved by ‘leadless’ devices. A leadless DBS, which is being developed by Artann Laboratories, uses a miniature piezotransducer incorporated in the implanted stimulator to generate an electrical signal at the target site and accurately focus acoustic energy from an external source. If successful, this technology could simplify the surgical procedure for DBS, and so reduce complications.

References

Pharmacological Treatment of Parkinson Disease: A Review. Connolly BS, Lang AE. JAMA. 2014;311:1670-1683.

Management of Parkinson’s disease: Current and future pharmacotherapy. Kakkar AK, Dahiya N. Eur J Pharmacol. 2015;750:74-81

Deep-Brain Stimulation – Entering the Era of Human Neural-Network Modulation. Okun MS. N Engl J Med 2014;371:1369-1373