Pharmaceutical companies are currently facing unprecedented challenges associated withconsequences of the last global financial crisis, patent cliff,loss in revenues from blockbuster drugs, etc. [1,2].Research programsin neurosciences are particularly affected by this turmoil.
Indeed, some Big Pharma have recently reduced R&D activities in neurosciences and even shut down their programs because CNS drugs (i.e., except those for psychiatric indications), are probably among the riskiest, hardest and most expensive to develop – e.g., a long tradition oflow approval rates for new molecular entities (NMEs), low efficacy, significant side effects, etc. [3,4].
In fact, there is still no medicine approved by regulatory authorities that can cure or significantly improve functions in patients with spinal cord injury (SCI), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington’s disease, neuropathic pain, Parkinson’s disease (PD)(except for levodopa) or Alzheimer’s disease (AD) .More than 1 billion people worldwide still suffer from diseases of the CNS .
Several reasons may explain this lack of potent CNS drugs – i.e., failure, at least until now, of stem cells or other repairing approaches as well as blood brain barrier issues associated with a limited access of many candidate medicines (except those with very small molecular weight) to target-brain cells.
Although several new approaches are currently being explored to de-riskand/or to improve the rate of approval of CNS drugs, one that may be considered as of particular interest is the multi-target approach. In brief, the latter could be characterized simply as an approach that consider and studyCNS diseases as complex and multi-target problems, instead of simple mechanisms with single targets.The multi-target approach explores the effects of combinatorial therapies (drug-device or drug-drug) for enhanced efficacy or synergistic effects through complementary action mechanisms.
For instance, in AD research, single targetsassociated with the amyloid cascade have attracted most of the attention in recent years. However, within thatcascade, multiple pathways could be targetedwith combination therapies to help balance the risk and increase the probability of at least one approach being successful. A cocktail of active moleculescould be used to increase the activity of α-secretase through agonism of Gq-coupled M1receptors and inhibit β- or γ-secretase activity or stimulate proteases that are important in Aβ catabolism such as neprilysin and plasmin [8-10].
In PD research, there has been compelling evidence showing that levodopa-induced effects are superior when patients are also given specific serotonergic or dopaminergic receptor agonists (e.g., sarizotan, rotigotine)[11,12].
Moreover, for the recovery of some walking capabilities in patients with SCI, reactivating concomitantly5-HT1A receptors and D1 receptors associatedwith lumbar spinal cord neurons can reactivate ‘dormant’ spinal circuits capable of producing neural activities that underlie basic locomotion[13,14]. A comparable approach has also been used to temporarily restore bladder and bowel control reflexively after SCI [15,16].
In conclusion, the ‘one-target-one-disease’ principle, for which corresponding NMEs and monotherapies have been the end result for decades,has generally failed in developing potent CNS drugs . The industryis bound, more than ever, to seek and choose new models for future innovationand sustained sales [18,19]. Identifying multi-target mechanisms and developing drug-drug combinations (e.g., fixed-dose combination products also known as FDCs) may yield improved approval rates and potent new therapies. In fact, in other areas such asasthma, HIV, canceror diabetesresearch, FDCs such as Atripla®,Advair®,Janumet®, to name a few, have become gold-standard therapies [17-19].
- Mukherjee S (2015)Three major trends driving layoffs in biotech and pharma.
- Pain EA (2011)Pharma industry in crisis. Science.
- Wegener G, Rujescu D (2013)The current development of CNS drug research. Integrative Journalof Neuropsychopharmacology16: 1687-1693.
- Skripka-Serry J (2013) The Great neuro-pipeline brain drain and why Big Pharma has not given up on CNS disorders. Drug Discovery World.
- Cutler NR, Sramek JJ, Murphy MF, Riordan H, Biek P, et al. (2010) Critical pathways to success in CNS drug developmentpp: 272.
- Data from WHO 2007 and German Ministry of Education and Research (2015).
- Pangalos MN, Schechter LE, Hurko O (2007) Drug development for CNS disorders: strategies for balancing risk and reducing attrition. Nature Reviews Drug Discovery 6: 521-532.
- Nitsch RM, Slack BE, Wurtman RJ, Growdon JH (1992) Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors258: 304–307.
- Pangalos MN, Jacobsen SJ, Reinhart PH (2005) Disease modifying strategies for the treatment of Alzheimer’s disease targeted at modulating levels of the β-amyloid peptide. Biochem. Soc. Trans 33: 553–558.
- Dominguez DI, De Strooper B (2002) Novel therapeutic strategies provide the real test for the amyloid hypothesis of Alzheimer’s disease. Trends Pharmacol23: 324–330.
- Bara-Jimenez W, Babbiani F, Morris MJ, Dimitrova T, Sherzai A, et al. (2005) Effects of serotonin 5-HT1A agonist in advanced Parkinson’s disease. MovDisord 20: 932-936.
- Ceballos-Baumann A, Hack HJ (2011)Rotigotine transdermal patch in combination therapy for Parkinson’s disease – observations in routine clinical practice. Curr Med Res Opin 27: 1899-1905.
- Guertin PA, Ung RV, Rouleau P (2010) Oral administration of a tritherapy for central generator activation in paraplegic mice: proof-of-concept of efficacy. Biotechnol J 5: 421-426.
- Ung RV, Rouleau P, Guertin PA (2012) Functional and physiological effects of treadmill training induced by buspirone and L-DOPA in clenbuterol-treated paraplegic mice. Neurorehabil Neural Repair 26: 385-394.
- Guertin PA (2009) Recovery of locomotor function with combinatory drug treatments designed to synergistically activate specific neuronal networks. Curr Med Chem16:1366-1371.
- GuertinPA (2016)New pharmacological approaches against chronic bowel and bladder problems in paralytics.World J Crit Care Med5:1-6.
- Wermuch CG (2004)Multitargeted drugs: the end of the ‘one-target-one-disease’ philosophy. Drug Discovery Today 9: 826-827.
- DiMasi JA, Hansen RW, Grabowski HG (2008)Misleading congress about drug development: Reply. Journalof Health Polit Policy Law. 33: 319-24.
- Mullard A (2014)New drugs cost US$2.6 billion to develop. Nature Reviews Drug Discovery 13: 877.