**3. Drug repurposing/repositioning for orphan diseases/disorders**

Approximately 7000 rare diseases are currently present in the world and more than 95% among these lack therapeutic agents approved by US-FDA [1]. The concept behind orphan disease might be many yet they have a single key point which is common that is the disease affects a minor part of the population. The definition of orphan diseases differs in different countries. In US, orphan disease is the one affecting fewer than 2 lakh people, in Japan the disease should affect fewer than 50,000 people to be called as orphan disease and in Europe the prevalence should be 5 in 10,000 [1, 22].

It is very challenging to develop new drugs for the treatment of rare diseases because the number of patients suffering from these diseases are very limited and are distributed over a vast geographical area. Another issue is of high variability among these diseases, influenced mostly by genetic factors. Financially, the development and subsequent production of these drugs is not viable for the pharmaceutical companies therefore drug repurposing for orphan diseases is a good option [22]. The patients requiring immediate treatment also do not have the luxury of more time at their disposal therefore a new strategy is needed so that the drugs are made available faster and cheaper to these patients. The pathology and various biochemical pathways of many orphan diseases are not very well known. Computational techniques will be a helpful option in the case where the underlying mechanism of the disease is not well understood. The advancement of the huge scale genomic sequencing project may lead to the understanding of the genetic variations that may be the cause of these diseases and it may lead to possibility of repurposing the drugs which are targeting the concerned protein [1]. There are few examples of repurposed drugs described in **Table 2**.

The approved drugs have already undergone intense testing like the safety studies, bioavailability studies and PK/PD studies and therefore drug repurposing leads to significant cost cutting and faster development [22]. Hence, this is an attractive prospect for the pharmaceutical industry as well. A total of 51 new medications reaching the market in 2009, the drugs which came to the market via the strategy of drug repurposing were 30% [23].

There are particular regulations designed to promote the research into orphan diseases and these rules could give market exclusiveness in circumstances repurposed agents cannot be protected by the patent. The Orphan Drug Act (ODA; 1983) was introduced for the first time which reflected the issues regarding the economics of drug development for orphan disease and how it was unfavorable. FDA has licensed about 360 agents for rare diseases since 1983 as compared to less than 50 agents before 1983 [24]. US legislation provides for faster FDA approval, tax incentives and funding support for research in orphan diseases. Market protection is also one of the incentives in which a generic form is not allowed to come to the market for 7 years. Tax concession, waiving of the regulatory fees are also the incentives which are provided. Similar legislation has been implemented in Singapore, Japan, Europe and Australia after the success of ODA, with each jurisdiction having a little bit of difference in the definition of the indication and the incentives to be provided [1].

#### *Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications*


#### **Table 2.**

*A few examples of repurposed drugs with their new indication.*

Another area of concern is the broad group of infectious diseases known to affect more than 1 billion population in tropical and subtropical areas [22]. Populations that are severely impacted are the people living below poverty line, not having appropriate sanitary conditions and in direct contact with contagious vectors or domestic animals [25]. The therapies currently present have many drawbacks like pricing and increase probability of drug resistance. Moreover, there are not much financial gains for investing money in developing drugs for these diseases as the patient population is unable to afford them [26]. Subsequently, given that the profit-making companies produce almost all the drugs, these firms will hardly be having any interest in investing in drug research and development which will not produce high financial returns. For this reason, development of therapies for these diseases becomes increasingly necessary. As discussed earlier that drug repurposing is an effective method due to various reasons, it can also be effectively used in this area where resources are limited and there is a huge need for productive therapies. Miltefosine, used for visceral leishmaniasis originally was antineoplastic agent whereas Amphotericin B used to treat fungal infections was repurposed for treating visceral leishmaniasis [22]. Other examples include Tamoxifen (agent for breast cancer) has shown to have anti-leishmanial activity, eflornithine (topical agent for hirsutism) has shown to be effective for sleeping sickness and auranofin (drug for rheumatoid arthritis) has shown to be effective against lymphatic filariasis and Onchocerca volvulus induced river blindness [27].

These days, multiple researches have demonstrated encouraging results in terms of repositioning supported by computational methods like chemical genomics screening for developing agents for such kind of diseases like schistosomiasis [28]. Some other examples where drug repurposing has shown promise for these diseases are vandetanib, trametinib and atorvastatin [29, 30].

**73**

*Drug Repurposing and Orphan Disease Therapeutics DOI: http://dx.doi.org/10.5772/intechopen.91941*

**4. Regulatory considerations for drug repurposing**

**5. Future perspectives of drug repurposing in orphan disease** 

against dengue virus [22].

market of orphan diseases.

tion in drug repurposing [1, 33].

**therapeutics**

therapeutics.

Drug repurposing strategies have also been used in the cases of viral diseases like Zika virus where FDA approved drug for hepatitis C which is Sofosbuvir has shown promising results [22]. The target of this drug is RNA polymerase which is present in Hepatitis C and Zika virus and has shown to reduce viral load in experimental studies [31, 32]. The same is the case with prochlorperazine by targeting the binding and the entry of the virus to host cells has shown to have a strong antiviral activity

Drug repurposing is cheaper and faster than the conventional methods and thus gives hope to the patients where the population suffering from the disease is much smaller and making the traditional model of drug discovery nonviable. A collective effort is required among all the stakeholders if already available drugs have to be repurposed. This approach helps in reducing the potential risks and the expense of developing a new agent, therefore having the ability of revolutionizing the drug

In the US, to get permission for drug repurposing, research and pharma companies need to file applications under suitable sections including 505(b)(1), or 505(b) (2) or 505(j), depending upon the regulatory paths. Further, the company needs to fill NDA type 6 and sNDA (supplemental new drug application) for new indication of drug, NDA type 3 for new dosage form and NDA type 4 for drug new combina-

As orphan disease affects a small percentage of the population, research and pharma companies face great challenge and burden in developing drugs for its management because of small market potential. Patients fail to get proper care, diagnosis and treatment. Even if the treatment is available, it is relatively expensive. Thus, drug repurposing can be of great help in orphan disease therapeutics. It saves both' the time and money involved in the drug development process. In October 2010, "Dr Ruxandra Draghia-Akli, the Directorate-General for Research and Innovation (DG RTD) of the European Commission (EC) and Dr Francis Collins, US National Institutes of Health (NIH)" at Reykjavík (Iceland), launched the International Rare Diseases Research Consortium (IRDiRC) to look after the drug and research development in orphan/rare diseases [34]. This consortium unites both government and private research funding societies to advance the drug development for orphan diseases at global level including task forces and drug repurposing in orphan disease

The research in rare diseases has already changed the global approach because earlier researchers were not much interested in repurposing the existing drug but some global breakthrough has really changed the minds of pharma companies and examples are alglucerase that was obtained from human placental tissue and was widely used for Type I Gaucher disease as a "first enzyme replacement therapy" and, it was also approved by FDA in 1991. However, it was withdrawn from the market due to adverse effect and already available drugs in the market which are prepared from recombinant DNA technology which are safe to use [35]. Fomivirsen which is an antisense oligonucleotide and was approved by FDA for

*Drug Repurposing and Orphan Disease Therapeutics DOI: http://dx.doi.org/10.5772/intechopen.91941*

*Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications*

**Drug Original indication New indication**

Sildenafil Angina Erectile dysfunction

Celecoxib Pain and inflammation Familial adenomatous polyps

Minoxidil Hypertension Hair loss Zidovudine Cancer HIV/AIDS

Atomoxetine Parkinson disease ADHD

Topiramate Epilepsy Obesity

*A few examples of repurposed drugs with their new indication.*

Raloxifene Osteoporosis Breast cancer Rituximab Cancers Rheumatoid arthritis Duloxetine Depression Stress urinary incontinence.

Fingolimod Transplant rejection Multiple sclerosis Bupropion Depression Smoking cessation Lidocaine Local anesthetic Arrhythmia

Aspirin Analgesia Colorectal cancer Ketoconazole Fungal infections Cushing syndrome

Dapoxetine Analgesia and depression Premature ejaculation

Thalidomide Morning sickness Erythema nodosum leprosum and multiple

myeloma

Another area of concern is the broad group of infectious diseases known to affect more than 1 billion population in tropical and subtropical areas [22]. Populations that are severely impacted are the people living below poverty line, not having appropriate sanitary conditions and in direct contact with contagious vectors or domestic animals [25]. The therapies currently present have many drawbacks like pricing and increase probability of drug resistance. Moreover, there are not much financial gains for investing money in developing drugs for these diseases as the patient population is unable to afford them [26]. Subsequently, given that the profit-making companies produce almost all the drugs, these firms will hardly be having any interest in investing in drug research and development which will not produce high financial returns. For this reason, development of therapies for these diseases becomes increasingly necessary. As discussed earlier that drug repurposing is an effective method due to various reasons, it can also be effectively used in this area where resources are limited and there is a huge need for productive therapies. Miltefosine, used for visceral leishmaniasis originally was antineoplastic agent whereas Amphotericin B used to treat fungal infections was repurposed for treating visceral leishmaniasis [22]. Other examples include Tamoxifen (agent for breast cancer) has shown to have anti-leishmanial activity, eflornithine (topical agent for hirsutism) has shown to be effective for sleeping sickness and auranofin (drug for rheumatoid arthritis) has shown to be effective against lymphatic filariasis and

These days, multiple researches have demonstrated encouraging results in terms

of repositioning supported by computational methods like chemical genomics screening for developing agents for such kind of diseases like schistosomiasis [28]. Some other examples where drug repurposing has shown promise for these diseases

Onchocerca volvulus induced river blindness [27].

are vandetanib, trametinib and atorvastatin [29, 30].

**72**

**Table 2.**

Drug repurposing strategies have also been used in the cases of viral diseases like Zika virus where FDA approved drug for hepatitis C which is Sofosbuvir has shown promising results [22]. The target of this drug is RNA polymerase which is present in Hepatitis C and Zika virus and has shown to reduce viral load in experimental studies [31, 32]. The same is the case with prochlorperazine by targeting the binding and the entry of the virus to host cells has shown to have a strong antiviral activity against dengue virus [22].

Drug repurposing is cheaper and faster than the conventional methods and thus gives hope to the patients where the population suffering from the disease is much smaller and making the traditional model of drug discovery nonviable. A collective effort is required among all the stakeholders if already available drugs have to be repurposed. This approach helps in reducing the potential risks and the expense of developing a new agent, therefore having the ability of revolutionizing the drug market of orphan diseases.

## **4. Regulatory considerations for drug repurposing**

In the US, to get permission for drug repurposing, research and pharma companies need to file applications under suitable sections including 505(b)(1), or 505(b) (2) or 505(j), depending upon the regulatory paths. Further, the company needs to fill NDA type 6 and sNDA (supplemental new drug application) for new indication of drug, NDA type 3 for new dosage form and NDA type 4 for drug new combination in drug repurposing [1, 33].
