Trikafta SHE Task - Grade: A PDF

Preview

Summary

Science as a Human Endaevour Task on the development of the Trikafta drug....

Description

Trikafta SHE Task Introduction Cystic Fibrosis (CF) is one of the most common recessive diseases in the world, currently affecting over 70,000 lives, predominantly impacting the Caucasian community with much of the CF population distributed in Western countries (FDA, 2019). The discovery of the mutated gene which produces defectively shaped CFTR channel proteins causing CF has played a key role in the recent development of the breakthrough CF treatment drug, Trikafta, which was created as per the revolutionary rational drug design (or rational design) method (Malcom, 2021; SciShow, 2019). The development of Trikafta was in accordance with some of the key SHE concepts including influence of breakthroughs in Computer Aided technology and genetic medicine which allowed for the identification of the protein CFTR, which was vital in the allowing for the implementation of the rational design method to develop Trikafta. The development of Trikafta was also heavily influenced by the social and ethical consideration taken by Vertex Pharmaceuticals and the FDA in the development and production of the Trikafta. Moreover, the key SHE concept of development was also addressed with the understanding that the use of modern drug design methods relied on previous evidence of specific biological molecules which played a role in a disease, such as the targeting of CFTR in the rational design method.

Relevance Cystic Fibrosis is a genetic disease caused by a mutation in the gene for the channel protein CFTR (FDA, 2019; Malcom, 2021; SciShow, 2019; Tiwari, 2021). The CFTR protein has fundamental applications in the in the windpipe and pancreatic region of the body, where cilia move mucus containing pathogens such as bacteria and viruses or molecules required by the body such as digestive enzymes secreted in the pancreas (Malcom, 2021; SciShow, 2019; Tiwari, 2021). Cystic Fibrosis occurs when the gene for CFTR produces faulty variations of the protein that cannot transport chloride ions into the mucus in order to attract water molecules, causing the mucus to become dry (Malcom, Figure 1: Shows the comparison of airway between healthy lungs and lungs with Cystic Fibrosis. (Mayo 2021; SciShow, 2019; Tiwari, 2021). Figure 1 shows the difference between a healthy airway, and one affected by cystic fibrosis, it is evident that the Foundation for Medical Education and Research, 2020) passage of the CF airway is significantly reduced (Mayo Foundation for Medical Education and Research, 2020). In a low moisture environment, cilia found in the trachea and pancreatic region cannot move mucus, trapping molecules which need to be removed or used by the body (Malcom, 2021; SciShow, 2019; Tiwari, 2021). Rational design is a pharmaceutical method which targets specific molecules in the body in order to inhibit or activate their function without affecting other parts of the body (Sun, 2015; Tiwari, 2021). Using this method, Vertex Pharmaceuticals developed Trikafta, which comprises of 3 primary molecules, tezacaftor, ivacaftor and elaxacaftor which have the necessary properties to allow for complementary binding to CFTR to correct its shape (FDA, 2019; BusinessWire, 2019). This would be achieved as per the allosteric inhibition model where the shape of the CFTR is changed is changed (Chen, 2013). The elaxacaftor molecule is only complimentary to CFTR produced by the F508del mutation, a deletion mutation that is common to over 66% of the CF community (Cystic-Fibrosis, 2020). The corrected form of the CFTR can greatly amplify the flow of chloride ions in the mucus, increasing the flow of water in out of the cells lining the trachea (SciShow, 2019; Tiwari, 2021).

Influence Development in the treatment of Cystic Fibrosis is one of the most significant goals in the scientific community, with CF being one of the most common life-limiting diseases in the world. Progress in fields of medicine and computerised drug design methods, particularly in their research of CF has heavily influenced the development of a revolutionary treatment in the form of the Trikafta drug. Thus, demonstrating the key SHE concept of influence. The genetic breakthrough in the medical community with the discovery of the cystic fibrosis causing gene allowed the Trikafta developer Vertex Pharmaceuticals to implement the method of rational design during the development of Trikafta (Surabhi, 2018; Cystic Fibrosis Foundation, 2021). The identification of the CFTR protein allowed Figure 2: Shows distribution of CF patients scientists at Vertex Pharmaceuticals to utilise the molecule elaxacaftor in based on age group. Graph shows number of Trikafta, which is comprises of the complementary binding property of the patients in all ages with 5 year increments drug corresponding to CFTR (Cystic Fibrosis Foundation, 2021; FDA, 2019). The use of computer-aided bio-simulations to understand the (Mehta, 2010). interaction between the drug and proteins in the body was a vital aspect of ensuring the reliability of Trikafta (Surabhi, 2018). This in turn enhanced the chance of acceptance by patients and also sped the clinical stage by eliminating the requirement of animal testing to become rapidly accessible by over 20,000 patients who are currently referring to life-limiting treatment methods such as oxygen therapy or lung transplants (Cystic-Fibrosis, 2020; Freitas, 2020). Furthermore, clinical trials of the drug as per the Australian Therapeutic Goods &

Administration show its compatibility with patients 12 years and over , which can be seen in figure 2 as an age group comprising of over 90% of the CF population, most of whom have limited access to an approved therapeutic option (Cystic Fibrosis Canada, 2020; FDA, 2019; Mehta, 2010; Therapeutic Goods and Administration, 2021). Additionally, the development and approval of Trikafta was an outcome of the social impact of CF and the ethical considerations in Trikafta’s development. This further address the key SHE concept of influence. In accelerated approval of Trikafta by the FDA in 2019 was due to the significant lung function improvement of patients in Trikafta’s clinical trial stages, which contrasts to the negative impact of current CF treatments , such as oxygen therapy or lung transplant which hinder the lifestyle of CF patients. This is particularly evident in the extensive time of participation required which further limits the lives of CF patients (CysticFibrosis, 202; Vertex, 2021). Oxygen therapy requires patients to refer to supplementary breathing machines to improve assist in oxygen intake, which could require up to daily usage for patients with severe breathing difficulty (Weatherspoon, 2017). Trikafta could enforce a treatment method for CF which is minimises the effect on patient lifestyle , as the use of drugs does not require rigorous participation unlike other treatments mentioned. The use of Rational Design addresses the ethical consideration taken by Vertex Pharmaceuticals to minimise unnecessary effect of the drug treatment on the overall health of patients by highly specifying the targeted molecule and leaving other vital cells and proteins which are not involved in the disease, unaffected (Sun, 2015; TEDx Talks, 2020). This reliable approach to safe medication has allowed for an amplified acceptance of Trikafta by patients, which is evident in the use of the drug by 60% of eligible patients (Cystic-Fibrosis.com, 2020). Moreover, Trikafta was designed to treat the F508del mutation, which is prevalent in over 70% of CF patients, hence maximising the proportion of the targeted population (FDA, 2019).

Development The 1989 genetic breakthrough in the discovery of the gene responsible for cystic fibrosis and the development of computer aided drug design (CADD) in 1981 provided vital evidence for the use of rational design technique in the development of Trikafta (Jamkhande, 2018; Marx, 1989). In the 1989 research by Lap-Chee Tsui, it was identified that the CFTR channel protein’s deformation causes minimal flow of water into the trachea resulting in dry mucus (Jamkhande, 2017; Marx, 1989; Surabhi, 2018). Likewise, evidence of the particular molecule causing CF enabled scientists at Vertex Pharmaceuticals to implement molecules which could force a more optimal shaping of the protein (Vertex, 2021). As per the method of rational drug design, Trikafta was developed using the 3 primary components, elaxacaftor, ivacaftor and tezacaftor (SciShow, 2019; Vertex, 2021). Clinical trials of Trikafta showed 10% greater lung function compared to the previous drug Symdeko which only contained tezacaftor and ivacaftor (Cystic-Fibrosis Foundation, 2021) . Figure 3 shows the advantage of positive clinical trials as Figure 3: Shows the process of expedition of they result in accelerated approvals and priority review to reduce time of Trikafta s by the FDA (Freitas, 2020). treatment review, allowing for more rapid accessibility by patients (Freitas, 2020; FDA, 2019). Furthermore, the method of drug design frequently relies on the utility of computer aided systems. Figure 3 demonstrates the role o f CADD in the understanding of interactions between molecules in the drug and humans. A computerised approach in the field of pharmacy can provide more precise and faster development of drugs which have highly predictable outcomes to minimise negative effect on patient health the outcome of which is evident in the expedition of Trikafta in Figure 3 (Freitas, 2020; Sun, 2015; Surabhi, 2018). The dependence on current and extensive procedures of CF treatments can be reduced in light of the Trikafta clinical trials, which have provided evidence towards a Figure 5: Helps to break severe Figure 4: Shows general representation of more lifestyle pro treatment. Thus, build-up of mucus, primarily used workflow of CADD- the method of developing highlighting the key SHE concept of drugs using computer aided design technology development with the introduction of by patients with serious symptoms, which also provides simulation of molecule a new treatment which has the price ranges from $10000-$15000 interaction in humans (Surabhi, 2018). potential to modify or potentially (RespirTech, n.d.) replace existing treatment methods (Cystic-Fibrosis, 2020; Freitas, 2019). Airway clearance technique is one of the most predominant choices for the CF treatment, however, the therapies involved such as pulmonary rehabilitation require a range of machines and intensive physical participation, resulting in a negative financial and lifestyle-limiting impact on patients (Weatherspoon, 2017). This is particularly evident in the requirement of airway clearance systems, which have a median cost of $10000, which is a major financial liability for future CF treatments (RespirTech, n.d.; Weatherspoon, 2017). Figure 5 shows a Respirtech inCourage Airway Clearance System, part

of the Airway Clearance treatment requiring daily participation for patients who engage in physical activity (RespirTech, n.d.). Additionally, an alternative treatment in the form of lung transplant comprises of numerous risks to patient safety, including further blockage of airways, blood clots, bleeding etc (Weatherspoon, 2017). Conversely, due to the implementation of rational design to develop Trikafta, the specific molecule targeting behaviour of the chemicals in the drug, allows for a treatment with limited supervision, in turn encouraging a positive lifestyle for CF patients as a result of greater privacy and independence of their treatment (Cystic Fibrosis, 2020; Cystic Fibrosis Foundation, 2021;Weatherspoon, 2017).

Conclusion The development of the revolutionary drug Trikafta for the treatment of Cystic Fibrosis has been influenced by breakthroughs and development in computer aided technologies and medicine in addition to the social impact of CF to evoke the necessity of a lifestyle focused treatment. Trikafta’s development was also in accordance with evidence from past research allowing Trikafta to not only alleviate symptoms greatly but rather have an all encompassing effect by improving lifestyle and eliminating financial liabilities unlike the treatments available today. Almost half of the CF community today refer to Trikafta as their primary treatment due to its pro lifestyle approach to fighting Cystic Fibrosis.

Word Count: 1527

Reference list

Primary Source Interview Tiwari, S 2021, ‘Cystic Fibrosis’. Journal Articles Jamkhande, PG, Ghante, MH & Ajgunde, BR 2017, ‘Software based approaches for drug designing and development: A systematic review on commonly used software and its applications’, Bulletin of Faculty of Pharmacy, Cairo University, vol. 55, no. 2, pp. 203–210. Marx, J 1989, ‘The cystic fibrosis gene is found’, Science, vol. 245, no. 4921, pp. 923–925, viewed 31 January 2020, . Mehta, G, Macek, M & Mehta, A 2010, ‘Cystic fibrosis across Europe: EuroCareCF analysis of demographic data from 35 countries’, Journal of Cystic Fibrosis, vol. 9, pp. S5–S21. Surabhi, S & Singh, B 2018, ‘COMPUTER AIDED DRUG DESIGN: AN OVERVIEW’, Journal of Drug Delivery and Therapeutics, vol. 8, no. 5, pp. 504–509, viewed 25 June 2021, . Zhiwei, C, Li, H, Chen, J-H & Shephard, D 2013, ‘Time for T...(T3, T4, rT3)? Focus on “Acute inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel by thyroid hormones involves multiple mechanisms”’, American Journal of Physiology-Cell Physiology, vol. 305, no. 8, pp. C800–C802, viewed 7 July 2021, . Books Sun, H 2015, A practical guide to rational drug design, 2nd edn, vol. 1, Elsevier/Woodhead Publishing, Amsterdam, p. 292. Videos

TEDx Talks 2020, Toward a Cure for Cystic Fibrosis: The Best Story in Medicine | Rebecca Schroeder | TEDxCoeurdalene, YouTube, viewed 1 July 2021, . Cystic Fibrosis Canada 2020, Trikafta research study presentation, YouTube, viewed 3 July 2021, .

Secondary Source Articles/Websites Cystic Fibrosis Foundation 2021, FDA Accepts Vertex Application for Expansion of Trikafta to Include Children ages 6-11, www.cff.org, Cystic Fibrosis Foundation, viewed 21 June 2021, . Cystic Fibrosis Foundation n.d., Elexacaftor + tezacaftor + ivacaftor (Trikafta®) | CFF Clinical Trials Tool, www.cff.org, Cystic Fibrosis Foundation, viewed 29 June 2021, . Cystic Fibrosis n.d., Current Treatments, Cystic Fibrosis.org, Cystic Fibrosis, viewed 2 July 2021, . Cystic-Fibrosis, 2020, The Trikafta Tidal Wave Of Hope, Cystic-Fibrosis.com, Cystic-Fibrosis.com, viewed 2021, . FDA 2019, FDA approves new breakthrough therapy for cystic fibrosis, U.S. Food and Drug Administration, viewed 15 June 2021, . Freitas, A 2020, Breakthrough Drug is a Breath of Fresh Air for Cystic Fibrosis Patients, Journal of Young Investigators, Journal of Young Investigators, viewed 3 July 2021, . Malcolm, E 2021, Trikafta for the Treatment of Patients With Cystic Fibrosis (CF), Cystic Fibrosis News Today, viewed 16 June 2021, . Mayo Foundation for Medical Education and Research 2020, Cystic Fibrosis, mayoclinic.org, viewed 22 June 2021, . Mehta, G, Macek, M & Mehta, A 2010, ‘Cystic fibrosis across Europe: EuroCareCF analysis of demographic data from 35 countries’, Journal of Cystic Fibrosis, vol. 9, pp. S5–S21.

Osakw, O 2016, Computer-Aided Drug Design, www.sciencedirect.com, Odilia Osakw, viewed 20 June 2021, . RespirTech n.d., InCourage | RespirTech, RespirTech, RespirTech, viewed 1 July 2021, . Team, C 2018, What happens when a clinical trial is completed | Clara Health, Clara Guides, Clara, viewed 2 July 2021, . Therapeutic Goods and Administration 2021, Trikafta, Therapeutic Goods Administration (TGA), Australian Government Department of Health, viewed 2 July 2021, . Vertex 2021, Vertex Receives Australian TGA Approval for TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor and ivacaftor) to Treat People With Cystic Fibrosis Ages 12 Years and Older Who Have At Least One F508del Mutation | Vertex Pharmaceuticals, investors.vrtx.com, viewed 1 July 2021, . Weatherspoon, D 2017, Oxygen Therapy | Definition and Patient Education, Healthline, Healthline, viewed 28 June 2021, . Videos BOC Sciences 2018, Computer aided Drug Design BOC Sciences, www.youtube.com, viewed 4 July 2021, . BusinessWire 2019, FDA Approves TRIKAFTA ..., www.youtube.com, YouTube, viewed 28 June 2021, . SciShow 2019, New Cystic Fibrosis Treatment a ‘Game-Changer’ | SciShow News, www.youtube.com, YouTube, viewed 30 June 2021, ....