Academic Drug Discovery: Repurposing to treat disease
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Why would you want to repurpose drugs made to treat one condition to treat other diseases?
The question is, why wouldn’t you want to? The current cost to get a drug to market is between $2-3 billion and takes 13-15 years. Worryingly, the ratio of the number of drugs produced per dollar spent on their development is deteriorating. This is because the number of new drugs produced each year has remained flat or constant for the past decade, whilst costs for their development have continued to rise1. All this means that drug development costs could become inhibitive and in turn be passed on to the patient, making it prohibitive for the patient to purchase their medicines.Repurposing or repositioning approved or failed drugs is the act of studying compounds already designed to treat one disease or condition to see if they are safe and effective for treating other diseases. As there is already a lot of detailed data on the efficacy and pharmacokinetic properties of the compound, they can progress through to market in ~6years, compared to the 13-15 years of conventional drug discovery, and at the cheaper cost1 of ~$300m.
Read more: drug discovery doesn't always have to start from scratch
Where do drugs fail?
Thousands of compounds enter the drug discovery pipeline but significantly less make it through to regulatory approval from bodies such as the Food and Drug Administration (FDA, USA) and European Medicines Agency (EMA, Europe). The time from discovery to preclinical development can take 6-9 years, and compounds that enter the pipeline have to cross the translation gap or Pharma’s ‘Valley of Death’2. So-called because of the number of promising compounds that fail to progress through from discovery to clinical trial, either due to lack of biological activity and suitability or from lack of investment.
Compounds can fail to progress through the various stages of development, be they target validation, lead optimization, process chemistry or preclinical testing. If a compound makes it through to phase I clinical trials they will already have received hundreds of millions of dollars of investment1.
Therapeutic drug discovery pipeline and the highlighted translation gap, or Pharma’s “Valley of Death”. So what makes a promising candidate for repurposing or repositioning? Broadly this falls into two categories. Compounds that have made it through the various stages of preclinical development that are shown to be safe in humans, but failed phase II trials as they did not improve the lives of sufferers of the condition for which they were initially intended. And, Generic pharmaceuticals that are outside of their protective patents3 can also make promising candidates.
Seizing the initiative
Initiatives to strike deals with major pharmaceutical companies to access their libraries of ‘failed’ drugs have been achieved in the UK by the Medical Research Council (MRC) and in the USA by the National Institute of Health’s National Centre for Advancing Translational Sciences (NCATS). These deals have led to the repurposing of drugs to treat a variety of diseases.
Freda Lewis-Hall, M.D., Chief Medical Officer at Pfizer, discusses the Discovering New Therapeutic Uses for Existing Molecules program at NCATS.
One such example to come from the MRC initiative has been the recent discovery that tradozone hydrochloride, a licensed antidepressant, had neuroprotective effects in a mouse model of prion disease4. The Group, headed by Prof. Giovanna Mallucci, had previously shown that a signaling pathway of the unfolded protein response was overactive in the brains of Alzheimer’s Disease patients. They performed a screen of 1040 compounds to discern if any interacted with the PERK/eIF2α-P branch of the unfolded protein response pathway, and found two hits. Both tradozone hydrochloride and dibenzoylmethane inhibited the overactive unfolded protein response which allowed protein translation to progress and prevented brain cell death and memory loss in mouse models of prion disease and frontotemporal dementia.
Read more: MRC researchers repurpose drugs, to treat dementia
Recently, NCATS Chemical Genomics Center Acting Branch Chief Dr Juan Marugan and Prof. Dean Burkin of the University of Nevada’s School of Medicine, Reno, lead a team of scientists that have identified a potential treatment for the degenerative muscle disease, Duchenne Muscular Dystrophy (DMD)5. The team screened more than 350,000 compounds and identified SU9516, previously developed as a treatment for leukemia, as a potential treatment for Duchenne Muscular Dystrophy. In stem cell and animal models, SU9516 raised levels of the cell structural protein integrin and promoted the formation of muscle cells and fibers, tissue lost in the degenerative muscle disease. The team are working with medicinal chemists to improve the specificity of the molecule and to remove the toxic anti-cancer components, to improve safety for future testing in patients.
Learn more: repurposing cancer drug to treat Duchenne Muscular Dystrophy
Shelton Bradrick’s and Mariano Garcia-Blanco’s groups at the University of Texas recently screened 774 FDA-approved compounds for their ability to block Zika Flavivirus infection. Their screen on HuH-7 cells revealed 20 compounds decreased Zika virus infection6. They were then able to test these 20 compounds on human cervical, placental, neural stem cells and human amnion cells to validate these compounds as anti-Zika infectives.
Work from Grant Churchill’s lab in Oxford resulted in the discovery that ebselen, a compound initially intended for stroke victims, could be repurposed as an alternative to lithium in the treatment of epilepsy7.
Other repurposed drugs of note are sildenafil, originally designed to treat angina but which was repurposed as Viagra8, and azidothymidine9 (Zidovudine), a failed chemotherapeutic repurposed as an antiretroviral to treat HIV/AIDS.
The repurposing revolution
As the cost of drug design and development continues to escalate, repurposing drugs offers faster and cheaper ways of treating disease. By making compounds available to academic researchers, initiatives such as the MRC’s and the NCATS’ are helping the drive towards repurposing through speeding up the process.
References:
- Scannell, J.W., Blanckley, A., Boldon, H. and Warrington, B., 2012. Diagnosing the decline in pharmaceutical R&D efficiency. Nature reviews Drug discovery, 11(3), pp.191-200.
- Society for Laboratory Automation and Screening. (2017). Bridging the Valley of Death: How Can Academia and Pharma Best Work Together?. [online] Available at: https://www.slas.org/eln/bridging-the-valley-of-death-how-can-academia-and-pharma-best-work-together/ [Accessed 29 Jun. 2017].
- Nosengo, N., 2016. Can you teach old drugs new tricks?. Nature, 534(7607), pp.314-316.
- Halliday, M., Radford, H., Zents, K.A., Molloy, C., Moreno, J.A., Verity, N.C., Smith, E., Ortori, C.A., Barrett, D.A., Bushell, M. and Mallucci, G.R., 2017. Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain, 140(6), pp.1768-1783.
- Sarathy, A., Wuebbles, R.D., Fontelonga, T.M., Tarchione, A.R., Griner, L.A.M., Heredia, D.J., Nunes, A.M., Duan, S., Brewer, P.D., Van Ry, T. and Hennig, G.W., 2017. SU9516 Increases α7β1 Integrin and Ameliorates Disease Progression in the mdx Mouse Model of Duchenne Muscular Dystrophy. Molecular Therapy, 25(6), pp.1395-1407.
- Barrows, N.J., Campos, R.K., Powell, S.T., Prasanth, K.R., Schott-Lerner, G., Soto-Acosta, R., Galarza-Muñoz, G., McGrath, E.L., Urrabaz-Garza, R., Gao, J. and Wu, P., 2016. A screen of FDA-approved drugs for inhibitors of Zika virus infection. Cell host & microbe, 20(2), pp.259-270.
- Singh, N., Sharpley, A.L., Emir, U.E., Masaki, C., Herzallah, M.M., Gluck, M.A., Sharp, T., Harmer, C.J., Vasudevan, S.R., Cowen, P.J. and Churchill, G.C., 2016. Effect of the putative lithium mimetic ebselen on brain myo-inositol, sleep, and emotional processing in humans. Neuropsychopharmacology, 41(7), pp.1768-1778.
- Goldstein, I., Lue, T.F., Padma-Nathan, H., Rosen, R.C., Steers, W.D. and Wicker, P.A., 1998. Oral sildenafil in the treatment of erectile dysfunction. New England Journal of Medicine, 338(20), pp.1397-1404.
- Fischl, M.A., Richman, D.D., Grieco, M.H., Gottlieb, M.S., Volberding, P.A., Laskin, O.L., Leedom, J.M., Groopman, J.E., Mildvan, D., Schooley, R.T. and Jackson, G.G., 1987. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. New England Journal of Medicine, 317(4), pp.185-191.
