The NGF System and its interplay with endocannabinoid signalling, from peripheral sensory terminals to the brain: new targets for the development of next generation drugs for neuropathic pain

Persistent pain, including NP, represents a major health problem and a sizeable economic and social burden, affecting 10-20% of the population, with total costs (health care and loss of work productivity) estimated to be around $ 600 billion in US and about € 300 billion in EU annually. One out of five adults on average suffers from moderate to severe CP in Europe, with an average duration of 7 years. This prevalence of the condition accounts for the loss of at least 500 million working days each year, with a cost to the European economy estimated to be €34 billion per year (DataMonitor Report, 2010).

Considering the aging European population and the CP increasing with elderly, the drugs costs will increase significantly. Most current therapeutic approaches are associated with unwanted effects and unsatisfactory pain relief. Therefore, an urgent need exists to develop more effective drugs that are directed towards new molecular targets. CP encompasses a diverse set of pathologies. Here we report pharmaceutical market data on pathologies more relevant for the treatments targeting the NGF system, such as OA, low back pain, and DNP. The value of the OA therapy market alone was estimated at 4.4 $ billion in 2010, with expected growth to be $ 5.9 billion in 2018. The global market for drugs to treat NP is estimated to increase from $2.4 billion in 2010 to $3.5 billion in 2018 (Nightingale, 2012).

  • The expected impact of our project is the development of novel therapies that modulate the neurotrophin pathways
    Four different antiNGF antibodies are currently under development by the industry worldwide.
    The market potential for the entire spectrum of uses for antiNGFs has been estimated to be around $11 billion per year (Holmes, 2012). In OA clinical trials, the analgesic efficacy of the antiNGF Tanezumab was shown to be very high and long lasting (Lane et al, 2010). The safety concerns associated with antiNGF treatment have strongly impacted the development of this class of agents, even though an FDA Advisory committee in March 2012 advised the hold on clinical trials to be relieved. This provides a significant opportunity to identify novel and safer therapeutics in this clinically-validated pathway and has a significant impact on the clinical use of antiNGF Mabs. The Consortium expects good marketability and rapid commercialization of the findings of PAINCAGE.
  • In this project, at least two products will be developed up to the end of preclinical testing: a soluble p75-Fc NGF scavenger, for different forms of neurogenic and NP and painless NGFR100 for DNP. What are the prospective market values of such second-generation NGF-based products? We can use as benchmark two market data concerning the acquisition prices for two of the current antiNGF Mabs. In 2006, Pfizer acquired the antiNGF Tanezumab program at a preclinical stage, for over $ 400 M. In 2009 Abbott acquired from Pangenetics the antiNGF PG110 Mab, which was at the commencement of clinical Phase I, for $ 190 M. If the compounds being examined in the proposal will live up the expectations in terms of efficacy and safety we can expect the same range value for p75NTR-FC and the painless NGFR100 programs, with a significant impact on the funding and growth of the institutions involved, as well as on European biotech industry. In addition, the information gained in the project will provide new validated targets (including sortilin and epigenetically regulated targets) for NP, that will be available for next generation drug development.
  • Finally, the knowledge gained on the interaction between the NGF and the EC system will provide a proof-of concept for the use of combined NGF-targeting and EC-targeting approaches, that may allow even better treatment or prevention opportunities.