Gauging The Role And Impact Of Drug Interactions And Repurposing in Neurodegenerative Disorders Part 5

6. Repurposed drugs for NDs

6.1. Repurposing of approved therapeutics for ND

Although there has been a lot of advancement in the drug discovery field from past decades to the present there still exist certain challenges associated with the complete cure of many diseases. 

As the human lifespan increases, memory problems among the elderly are becoming more of a concern. Disease and memory are closely related. Although certain diseases may adversely affect memory, a positive attitude, and healthy living habits can improve our memory.

First of all, mental problems such as depression and anxiety are closely related to symptoms of memory loss. This shows that people's mental health is closely related to memory. Therefore, we must maintain a positive attitude, face setbacks and difficulties bravely, communicate with friends frequently, maintain good interpersonal relationships, and make ourselves feel comfortable and relaxed.

Secondly, the impact of physical health on memory cannot be ignored. Chronic diseases such as diabetes, high blood pressure, and heart disease are all related to memory loss. Therefore, we should focus on preventing these diseases. Maintaining healthy living habits, such as regular eating and sleeping, a healthy diet, and appropriate exercise, can help enhance our body's resistance and thus improve memory.

In short, memory and disease are closely related, but we have preventive measures. We can improve our memory by maintaining a positive attitude, maintaining a healthy lifestyle, treating diseases in time, and paying attention to nutrition and other means. People such as the elderly, children, and students, should always pay attention to these issues to protect their health and quality of life. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also promote the growth and repair of nerve cells, thus enhancing the connectivity and function of neural networks. These effects can help improve memory, learning, and thinking speed, and may also prevent the development of cognitive dysfunction and neurodegenerative diseases.

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A new drug discovery program takes more than 10–12 years to bring the new drug into the market and this process involves a lot of money investment (Parvathaneni et al., 2019). The new drug also has to go through strict regulatory processes before its market approval. 

There are lot many molecules that enter the preclinical trials every year but only a few (1 in 10,000 molecules) of which can pave their path into the clinical studies (Basavaraj and Betageri, 2014). These limitations associated with the new drug discovery encourage pharmaceutical companies as well as researchers to utilize the already approved drug molecules for new indications. 

Investigational drug molecules that have failed to show efficacy for their predetermined indications also have chances to their efficacy for new indications (Parvathaneni et al., 2019; Pushpakom et al., 2019). This strategy of utilizing already approved or investigational drug molecules for new indications is known as drug repurposing/repositioning/re-profiling (Martin and Bowden, 2019). 

Unmet clinical needs have become one of the hurdles to the effective therapy of many diseases like cancer, ND, etc. Focusing only on ND including PD, AD, etc. is debilitating as their pathophysiology involves heterogeneous molecular mechanisms (Gitler et al., 2017). 

ND is caused due to progressive dysfunction and loss of neurons which lead to impairment in motor and/or cognitive functions (Giorgini, 2013; Budd Haeberlein and Harris, 2015). Various therapeutics have been approved by different regulatory agencies for the treatment of various types of ND. However, most of them are known to provide symptomatic relief along with a reduction in cognitive and motor functions (Hilbush et al., 2005). 

For the successful therapy of ND, the drug molecules must act on molecular mechanisms involved in the disease's development and progression. Recent clinical trials have shown failures to newly developed diseases modifying therapeutics and these failures lead pharmaceutical companies and researchers to focus on drug repurposing in ND. 

The clinical trial study of these repurposed drugs has shown promising results for the treatment of ND.

6.2. Advantages and challenges associated with the repurposing of drugs

6.2.1. Advantages associated with the repurposing of drugs

One of the important advantages of drug repurposing is the regulatory approval process becomes easy as compared to new drug entities. This is because the already approved drugs possess the accepted safety and tolerability level in humans which leads to a reduced risk of failure (Jourdan et al., 2020). The already-established safety will further avoid unanticipated obstruction in the trial phases (Strittmatter, 2014). 

The period required for the drug development will be condensed because of the availability of various data sets associated with preclinical analysis including safety and formulation development in certain cases (Pushpakom et al., 2019). 

 Another important advantage is less investment in drug development but it will depend upon the developmental stage and process of the repositioned drug candidate. These advantages offered by repurposing further increase the probability of the introduction of repurposed drug candidates into the market. 

But certain factors should be taken into consideration including formulation, dosage form, and route of administration of the repurposed drug as these factors may affect the drug's safety profile. Hence in such cases, re-evaluation of safety is required (Jourdan et al., 2020).

6.2.2. Challenges associated with the repurposing of drugs

Various drugs have been successfully repurposed for several disease conditions; however, it is not always fruitful for all the repurposed drugs. Drug repurposing poses certain challenges when it comes to patent considerations and regulatory aspects along with organizational barriers (Pushpakom et al., 2019).

6.2.2.1. Patent considerations. 

When the repositioned drug does not possess market approval then it becomes an advantage for the repositioner to apply for patent protection for the repurposed drug for a new indication. However the drugs being used for the repositioning are not new, hence there may be the presence of prior art which might lead to a repurposed drug being unpatentable (Ashburn and Thor, 2004). 

For off-patent drugs, there exists another issue relating to the use of formulations and dosage forms used by generic drug manufacturers. 

This is because the generic drug manufacturer makes use of the 'skinny labeling' strategy where they legally label their generic drug product solitary for non-patented indications. This may lead to a reduction in profitability as there may be difficulty in the stoppage of off-label usage for newly patented repurposed indications (Pushpakom et al., 2019).

6.2.2.2. Regulatory aspects. The regulatory aspects are the critical elements during the repositioning of drugs. Various regulatory pathways are available depending on the regulatory agencies for the application of repositioned drugs. 

Several regulatory agencies offer different exclusivity periods for the marketing of repurposed drugs but the offered timeline is not sufficient to make revenues out of it for the regaining of the invested money in the repurposing of drug candidates (Pritchard et al., 2017; Breckenridge and Jacob, 2019).

6.2.2.3. Organizational barriers in the pharmaceutical industry. 

Many pharmaceutical industries are working on drug repurposing in areas other than their primary disease area. For repurposing in such cases, these industries work in collaboration with academic organizations and smaller biotech companies (Pushpakom et al., 2019; Novac, 2013). 

The industries face certain organizational barriers when the area of focus of the organization doesn't match with that of the industry expectations and if the compound of interest has been discontinued from the organizational research and development (R&D) divisions which leads to the lack of support for the new indications (Ashburn and Thor, 2004). 

This led to the lack of personnel who can work on the projects designed for the repurposing of a drug in the designated diseased area along with a lack of funding and resources for the headway of the idea within the industry. These barriers can be overcome by the utilization of external resources such as contract manufacturing organizations, pharmacovigilance, and regulatory support (Pushpakom et al., 2019).

6.3. Intellectual property consideration for repurposed therapeutics

The pharmaceutical companies working on drug repurposing seek patent protection to gain an exclusivity period after commercialization to get revenues in return for investments made for the commercialization of repurposed drug molecules (Cavalla, 2013). 

As stated earlier, the patentability of a repurposed drug may be challenging as these drugs are not new to the researchers hence there may be a presence of prior art. The prior existence of such patents may become a hurdle for the commercialization of such repositioned drugs (Ashburn and Thor, 2004). However, there are various ways to tackle this situation while a patent application for repurposed drugs. 

One of which is the patent protection by the composition of matter (COM) of the product. This type of patent is considered the strongest strategy for patent protection. It covers active pharmaceutical ingredients (API) contained in the product, novel formulations, and drug delivery mechanisms. 

Nonetheless, the application for the composition of matter for API and formulations occurs early in the development phase of a new drug product which leads to a short patent life till the product reaches the market as compared to the time and money invested in bringing this product to the market (Smith, 2011). 

This barrier can be overcome by the new COM protection with the help of the inclusion of a new patentable chemical entity in the repositioned drug product, delivery mechanisms which can be a patentable or else patentable combination of APIs. 

In some cases, the repositioned drug would be off-patent and hence generic (Smith, 2011). In these situations, the repositioner can file a Method of Use (MOU) or only 'use' patent especially when the drug has never been marketed (Ashburn and Thor, 2004).

6.4. Regulatory consideration for repurposed therapeutics

For the development of repurposed drugs, regulatory considerations are important elements. Considering two major regulatory markets; Europe and the United States (US), types of applications, pathways for regulatory submission, and exclusivity benefits differ which are discussed in the following section of the article. 

In the US, new drug application is classified into different chemical types including new drug application (NDA) type 1 (new molecular entity), NDA type-2 (new active ingredient or new derivative), NDA type-3 (new dosage form), NDA type-4 (new drug combination), NDA type-5 (new formulation or new manufacturer), NDA type-6 (new indication). 

These applications can be filed under three possible regulatory pathways i.e. 505(b)(1), 505(b)(2), and 505(j) (Murteira et al., 2014). For minor changes such as labeling, new dosage forms, and strength in a product that is already approved as an NDA, a supplemental NDA has to be submitted by a company (Pushpakom et al., 2019). 

In the European Union, applications for repurposed drugs can be filed under three possible routes such as centralized, decentralized, or national application. Articles 6, 8(3), 10(3), and 10a of Directive 2001/83/EC partially include different drug repurposing strategies (Murteira et al., 2014). The regulatory filing for a new chemical entity in the US will be given five years as the initial period of exclusivity. 

But for previously approved activity which showed new clinical investigation such as new users will be given three years of additional exclusivity. In Europe, new chemical entity filing will be given as eight years of grant for marketing authorization during this period no generic company can make use of investigators' data while two years of two years will be provided during which generic company can only rely on the data produced by investigator but cannot market the product. 

During eight years of exclusivity, if the investigator identifies a new indication then 1 year extra exclusivity period will be given to the investigator given that this new indication provides substantial value as compared to existing therapies (Breckenridge and Jacob, 2019).

6.5. Potential repurposed drugs for various ND

In the case of ND, the function of neuronal cells in the brain is majorly affected thereby disturbing the quality of life. As said earlier there are various drugs already approved for the treatment of different ND but these are targeting only symptomatic relief there is an absence of disease-modifying therapies due to a lack of complete understanding of the underlying mechanism of actions. 

Repurposing of already approved drugs opens a promising therapeutic route for the management of such debilitating ND. In the following section, we have provided potential repurposed drugs for the management of various NDs.

6.5.1. Parkinson's disease

PD is the most commonly observed movement disorder. It occurs due to the loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc). The loss of dopaminergic neurons in SNpc leads to the deficiency of dopamine in SNpc which is responsible for the majority of PD symptoms (Dauer and Przedborski, 2003). 

The pathophysiology of PD is complex but it is not fully understood. It has been observed that the accumulation of Lewy bodies represents an important marker in the neuropathology of PD (Reddy et al., 2014). The current therapy is dependent on dopaminergic drugs and there are no established disease-modifying therapeutic options available for PD (Athauda and Foltynie, 2018). 

Also, there are side effects associated with the available therapies e.g. delivery of dopamine in the extra-striatal region, poor permeability across the blood-brain barrier, and variations in absorptions (Stoker and Barker, 2020). 

This shows the higher unmet clinical needs for the therapeutic management of PD and one of the options for overcoming such unmet clinical needs is the repurposing of already approved drugs.

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