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Drug Repurposing in the 21st Century

Drug Repurposing in the 21st Century

Old for New: Drug Repurposing in the 21st Century


The attractiveness of repurposing
The cost of finding, developing and achieving marketing approval for new, clinically effective drugs is immense and generally outside the purview of small companies unless they team up with established players. A growing, though not new, trend is the repurposing (also referred to as repositioning ) of approved drugs for additional indications. For our purposes, “approved” implies that the drug has at least satisfied the safety requirements of a Phase 1 clinical trial even if it has not yet achieved marketing approval. It has been estimated that it takes on average from $2-3 billion (USD) to develop a new drug1,2. In contrast, an estimated budget of $300 million may be sufficient to launch a repurposed drug, since repurposing takes advantage of previous sunken costs and clinical success. Publically available preclinical and early human data for these agents frequently sheds light on key aspects of safety, pharmacology and time-dependent efficacy for the agent aimed at an alternative indication. This information allows further streamlining of its development. Although the exact comparative figures are contested, there is no doubt that repurposing is an attractive option, especially when used to identify leads for diseases featuring complex etiology. In recent years, repurposing became an equally viable option for both established pharmaceutical companies seeking to expand their pipeline as well as for resource-starved start ups.


Drug repurposing is not new. For example chloroquine was first widely used to treat malaria in 1946. Since that time, it has been prescribed for 392 different diseases3. Another drug, chlorpromazine was developed in the early 1950s also for malaria use. Whilst it proved ineffective for this indication, it did display anti-psychotic properties and has been used for 394 different diseases. However, even this extensive repurposing has been dwarfed by that achieved with a steroid, prednisolone, which has been used in over 1340 indications. Such widespread repurposing of a small number of approved drugs has as a common thread, the drive to treat disease symptoms rather than the disease itself; corticosteroids like prednisolone, are effective anti-inflammatory drugs and inflammation is a well known feature of numerous diseases.

Sometimes the fact that different diseases can share overlapping pathologies can guide insightful repurposing efforts: Rapamycin was developed as an anti-transplant rejection drug. It works by modulating the host’s immune system. It has now found a role in combating the rare pediatric blood disease, Autoimmune Lympho Proliferative Syndrome, that affects young children, often killing them in their teens.


Taking a medicine from sinner to savior
Much rarer are repurposing examples where the new indication(s) represent a completely different therapeutic situation and the drug’s efficacy was not predictable. Thalidomide is one such example. The drug achieved infamy circa 1960 when its use during pregnancy to ameliorate morning sickness, resulted in horrendous limb malformations in the newborn. Nonetheless, the drug was reborn subsequently as an effective agent against the skin lesions caused by leprosy and then approved for treatment of multiple myeloma.


Identifying the next
Historically, repurposing was often driven by off label prescriptions mediated by physicians who noted similarities in the way different diseases presented. Today, various “omics” approaches can tease out overlaps in the molecular pathologies associated with different diseases and encourage repurposing activities. Paradoxically, the same frenetic pace of technology development can also render facile the large scale empirical screening of whole libraries of approved drugs in order to spot a repurposing candidate so long as a good in vitro assay is available.


The upside and the downside…
The above review would seem to make a compelling case for any drug developer at least considering existing drugs for new indications where no satisfactory treatment exists. However, the commercial case for repurposing is complex and many companies are not convinced the path forward is clear. Below, we will list the advantages and disadvantages of repurposing from the point of view of a for-profit company:



a. The drug has successfully completed at least Ph 1 safety trials; this removes significant risk and presages a much quicker regulatory pathway
b. Much of the drug development costs have already been incurred by others
c. The drug may be off patent or of short-lived remaining patent protection;
d. For a rare disease, seven years market exclusivity and other benefits may be available from the FDA if the drug is granted Orphan Drug Status (ODD) for the specific new indication
e. Even if the drug is already on the market for a different indication, it can go through the 505 (b)2 Regulatory pathway and get 3 years market exclusivity if further clinical data needed.      This can be 5 years if the new molecular entity has never received any market authorization in any form in the US.
f. There will be a lot of clinical and non clinical information existing regarding the drug development and patient responses
Methods of use patent could be available to protect a known drug in a novel indication



a. All historical data on the drug may not be made available to the aspiring “repurposer”, moreover for new indications there may be a need for additional pre-clinical animal studies to justify specific human treatment protocols;
b. Similarly, clinical trials ought to be congruent with the specific disease pathology and might even include additional time-dependent safety and efficacy assessment if the intended regimen including dosing, frequency, duration or route of administration differ from that used previously.
c. Although repurposing generally offers a cheaper development route, it still commands a formidable budget.
d. Despite of the initial promising clinical data, many drugs (new or repurposed) can still fail at Ph 2 or Ph 3 trials due to the unfavorable safety-efficacy profile or short-lasting effect(s) on disease pathology;
e. If the drug is off patent and available at low cost, it may be very difficult to make money out of it (but see Advantages e) above)
f. Even if the drug is patented for the new indication, off label use could erode profits assuming the drug is still around for the primary indication and cheaper


A comparison of the pros and cons would indicate that for a for-profit organization, repurposing makes best sense when the following conditions apply:

a. The drug/indication combination is granted ODD or some other type of definitive market exclusivity
b. A patent is granted for the new method of use.
c. The clinical development pathway is robust and the treatment regimen follows the original Ph1 trial.
d. The drug had previously passed through Ph1 trials but had failed to gain marketing authorization in the original indication (i.e. no price issue)
e. The drug is off patent or going off patent during the initiation of pivotal clinical trials (Ph2/3)
f. The drug works well in diverse, disease-specific in vitro assays as well as in animal models of the human disease exhibiting clinically relevant pathologies.


Repurposing drugs for neuromuscular disease
Genea Biocells (GBC) works with a number of rare neuromuscular diseases . It has developed a proprietary drug screening platform using skeletal muscle cells made from human pluripotent stem cells. It has a major focus on facioscapulohumeral muscular dystrophy (FSHD). GBC is currently repurposing a drug called GBC0905 to treat FSHD and is pleased to announce that it is currently conducting IND-enabling studies. In May 2018, Genea Biocells received ODD from the US FDA for the use of GBC0905 to treat FSHD


Nosengo (2016) Nature 534 314-316
Azvolinsky (2017) The Scientist, January Issue
Baker et al (2018) Drug Discovery Today 23 661-692


Alan Colman, July 20, 2018



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