Therapeutic focus - Parkinson’s disease in need of fresh impetus

Analysis

For a disease that was formally classified nearly 200 years ago and affects an estimated four million people worldwide, the fact that one drug, L-dopa, which was introduced over 40 years ago, remains the best treatment option available today to sufferers of Parkinson’s disease must rank as one of the biggest disappointments in the history of clinical research in the pharmaceutical industry.

Whilst the phase III results announced this week for Merck Serono and Newron Pharmaceuticals’ safinamide were encouraging, the fact that most experts believe the drug will at best provide a modest improvement to current treatments highlights the painfully slow progress of current research into Parkinson’s. This lack of breakthrough treatments is causing some experts, such as Peter Jenner, Professor of Pharmacology at King's College London, to warn that Parkinson’s research could go the way of stroke research, which is now almost negligible following a number of massive setbacks which caused big pharma companies to turn their backs on the area.

Shrinking market

According to forecast data from EvaluatePharma, the Parkinson’s disease market, which was worth $3.22bn in 2008, is set to decline 3% per year to $2.74bn by 2014.

Although some revenue growth is expected from some recently launched products, such as UCB’s Neupro and Teva’s Azilect, the cause of the overall decline is clear when considering that all five of the biggest-selling drugs in 2008 will be exposed to generic competition by 2014.
 

Anti-Parkinson's Disease Market: growth drivers and brakes 2008 - 14 WW annual sales ($m)
  Product Generic Name Pharmacological Class Company Phase Patent Expiry 2008 2014 Total Change (08 - 14)
Growth Drivers              
1 Neupro rotigotine Dopamine D2 & D3 agonist UCB Marketed Mar 2021  93  566  474
2 Azilect rasagiline mesylate MAOB inhibitor Teva Pharmaceutical Industries + Lundbeck Marketed Feb 2017  134  406  272
3 Pardoprunox (SLV 308) pardoprunox 5HT1A (serotonin) agonist & dopamine D2 partial agonist Solvay Phase III Dec 2019  -  129  129
4 Duodopa carbidopa & levodopa Dopa decarboxylase inhibitor Solvay Marketed Jan 2014  56  145  89
5 SCH 420814 preladenant Adenosine A2A receptor antagonist Schering-Plough Phase II -  -  50  50
                   
Growth Brakes              
1 Sifrol/Mirapex pramipexole Dopamine D3 agonist Boehringer Ingelheim Marketed Oct 2010  1,037  402  (635)
2 Requip ropinirole hydrochloride Dopamine D2 agonist GlaxoSmithKline Marketed May 2008  493  198  (295)
3 Comtan entacapone COMT inhibitor Novartis + Orion Marketed Oct 2013  543  288  (255)
4 Madopar levodopa & benserazide Dopamine precursor Roche Marketed -  287  81  (206)
5 Cabaser/Dostinex cabergoline Dopamine D2 antagonist Pfizer + Kissei Pharmaceutical Marketed Dec 2005  166  27  (139)
                   
Other products           336 449 113
Total           3,223 2,741 (483)

Parkinson’s, a degenerative disorder that impairs motor skills, speech and multiple other functions such as bladder control, is caused by insufficient formation and action of dopamine in the brain.

L-dopa, or levodopa, which is converted into dopamine by enzymes in the brain, remains the best treatment option and can significantly improve the lives of Parkinson’s patients. However, only 1-5% of L-dopa reaches its target receptors, the remainder of which is metabolised elsewhere in the body, causing serious side-effects. In addition, introducing L-dopa can cause a negative feedback loop on the formation of naturally occurring L-dopa, a process which can eventually become counterproductive.

As a result, the majority of new therapies launched within the last ten years have focused on various other ways of stimulating the production, or preventing the breakdown, of dopamine, such as dopamine agonists which target specific dopamine receptors.

Single or multiple target approach?

However, it is this more specific, single target approach, which could be one of the reasons that newer drugs have failed to provide the significant breakthrough that patients have been craving.

Whilst GlaxoSmithKline’s Requip and Boehringer Ingelheim’s Mirapex target the D2 and D3 receptors respectively, L-dopa targets all 1-5 dopamine receptors.

Professor Jenner believes that rather than the single-target screening approach much loved by the majority of pharma companies: “what we actually need is more ‘dirty drugs’, which can hit the most number of targets as possible”.

However, a review of current pipeline candidates for Parkinson’s reveals that a number of research products are still adopting the single-target strategy.

Parkinson's disease agents - selected phase III & II pipeline candidates   WW annual sales ($m) WW Peak Sales ($m)
Phase Product Generic Name Pharmacological Class Company Launch 2010 2012 2014  
                   
Phase III Pardoprunox (SLV 308) pardoprunox 5HT1A (serotonin) agonist & dopamine D2 partial agonist Solvay  2012  -  74  129  -
  Safinamide safinamide Dopamine reuptake inhibitor Merck KGaA  2010  -  18  35  467
  KW-6002 istradefylline Adenosine A2A receptor antagonist Kyowa Hakko Kirin  2010  -  21  31  310
  V1512 melevodopa & carbidopa Dopa decarboxylase inhibitor Vernalis  2010  0  1  2  58
                   
Phase II SCH 420814 preladenant Adenosine A2A receptor antagonist Schering-Plough  2012  -  17  50  338
  Aplindore aplindore Dopamine D2 agonist Neurogen  -  -  -  -  1,121
  BIIB014 - Adenosine A2A receptor antagonist Biogen Idec  -  -  -  -  343
  ProSavin - Dopamine gene therapy Oxford BioMedica  -  -  -  -  192
  CERE-120 - Neurturin gene therapy Genzyme  -  -  -  -  -
  JP-1730 fipamezole Alpha 2 receptor antagonist Santhera Pharmaceuticals  -  -  -  -  -
  SYN-115 - Adenosine A2A receptor antagonist Synosia Therapeutics  -  -  -  -  -
  V2006 - Adenosine A2A receptor antagonist Vernalis  2011  -  -  -  -
  OS - 320 - Anti-Parkinson's agent Osmotica Pharmaceutical  -  -  -  -  -
  OS - 352 - Anti-Parkinson's agent Osmotica Pharmaceutical  -  -  -  -  -

Non-dopamine approaches

“I was initially very bullish about non-dopamine approaches to treatment, but have become increasingly jaded by the increasing number of failures in this area”, says Professor Jenner.

The biggest most recent disappointment was the FDA’s rejection a year ago of Kyowa Hakko Kirin’s istradefylline, an Adenosine A2A receptor antagonist, which had been held up as a potential breakthrough treatment.

With another four Adenosine A2A receptor antagonists currently in phase II trials, the hope must be that the failure of istradefylline was more down to poor trial design, as some have argued, than a fundamental lack of activity for this new class of drug.

Hopes and fears

Of the other pipeline candidates, Professor Jenner believes gene therapies, such as Oxford BioMedica’s ProSavin, could ultimately provide a breakthrough treatment, although the recent failure of Genzyme’s neurturin gene therapy candidate, CERE-120, suggests the road to clinical success will be a rocky one.

However, with a number of high profile clinical failures in the sector, Professor Jenner is concerned that research into Parkinson’s could go down the “stroke route”; after pumping billions of dollars into new stroke treatments and producing nothing to show for it, the industry has now largely halted further research.

The ever decreasing number of product deals in the sector in recent years, with just two deals in the entire industry last year, suggests these fears may be materialising already.

Count of anti-Parkinson's product deals per year
Year Count of deals
 2008  2
 2007  6
 2006  6
 2005  4
 2004  9
 2003  5
 2002  5
 2001  4
 2000  5
 Total  46

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