Symdeko Drug: Mechanism of Action for Cystic Fibrosis Treatment

This report provides a comprehensive analysis of Symdeko, a medication used in the treatment of cystic fibrosis (CF). The report begins by defining CF as a progressive genetic disorder characterized by lung infections and breathing difficulties, highlighting the role of Symdeko in slowing disease progression. It delves into Symdeko's mechanism of action, emphasizing the combined effects of ivacaftor and tezacaftor in targeting CFTR protein defects and improving chloride transport. The report also discusses Symdeko's clinical effectiveness, FDA approval, and its ability to address specific CFTR mutations. Furthermore, it explores the different classes of CFTR mutations and how Symdeko's components, ivacaftor and tezacaftor, are designed to treat specific mutations. The report concludes by emphasizing the importance of tailoring treatments to the specific CFTR mutation to ensure the best therapeutic outcomes. The report references several research papers to support its findings, providing a detailed overview of Symdeko's role in CF treatment.

Running head: SYMDEKO™ FOR CYSTIC FIBROSIS
SYMDEKO™ for cystic fibrosis
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SYMDEKO™ FOR CYSTIC FIBROSIS
Table of Contents
Question 1:.................................................................................................................................2
Question 2:.................................................................................................................................2
Question 3:.................................................................................................................................2
References:.................................................................................................................................4

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SYMDEKO™ FOR CYSTIC FIBROSIS
Question 1:
Cystic fibrosis is a progressive genetic disorder that leads to the persistent infections
in the lung and also limits the breathing power of the victim as well. Although the disease has
not effective cure, very few choices of life saving medication is available that can slow down
the progress of the disease (2). Symdeko is one such medicine which is given to the patients
that are suffering from cystic fibrosis. The mechanism of action of this drug is complex, it
contains a combination of ivacaftor and tezacaftor, and both of the active agents perform
inter-related actions to target the clinical manifestations of cystic fibrosis. Elaborating further,
the Tezacaftor targets the defective CFTR protein and moves it onto the cell the
surface. Ivacaftor on the other hand helps to facilitate opening of the chloride
channels on the surface of the cell to enhance the chloride transport (1). Hence,
tezacaftor works as the corrector which helps in the movement of the defective
CFTR protein to the membrane so that it can successfully transport chloride
and the ivacaftor, helps in improving the flow of chloride over the cell
membrane by enhancing the length of time of the calcium channel improving
the ion and water transport and inhibits production of thick and sticky mucous.
Question 2:
Symdeko has been a new drug that has been introduced in the clinical care for cystic
fibrosis. As mentioned by the Gentzsch et al. the new drug Symdeko having the combination
of ivacaftor and the corrector tezacaftor had been effective in reversing the harmful effects of
the most common CFTR protein mutations. Along with that, this particular precision
medication has also been approved by the FDA and has been set to be released in European
market for the effectiveness of the drug (1). Ivacaftor, a component of the Symdeko, which is
also called Kalydeco, has also been approved by the FDA as a standalone cystic fibrosis
treatment as it can directly improve the calcium channel transport of the cell membrane by

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SYMDEKO™ FOR CYSTIC FIBROSIS
increasing the length of time of the channel opening facilitating better flow. Hence, it can be
considered that this drug providing the combining impact of ivacaftor along with corrector
tezacaftor, had been effective till date for treating selective CFTR mutations (3).
Question 3:
There are a variety of different mutations caused in the CFTR coding region that can
lead to the development of the cystic fibrosis in the patients (4). It has to be mentioned, not
all of the mutations can be treated by the same medication. Elaborating more, the mutations
to CFTR gene that has been identified in the last few years of research have been categorized
in 5 different major classes of mutation. Among the 5 classes of mutation of the CFTR, the
class I, II, and III have been pegged as the most severe of the mutations in the CFTR gene
leading to severe pancreatic insufficiency and decreased survival. On the other hand, the class
IV and V have been categorized as the mild mutations associated with pancreatic sufficiency
(2).
Hence, the mutations each have different trajectory of alterations in the physiological
functions and different to different clinical manifestations. Hence, for treatment as well, the
medications that are being utilized must take into consideration the particular type of
mutation, or at least the class, so that the exact alterations can be reversed and cellular
functions can be reversed. In case potentiator drugs are used it facilitates the movement out of
the ER. For instance, the Symdeko has two components, ivacaftor that targets the G551D
mutation and tezacaftor that targets the F508del mutation, hence this medication will yield
fruitful results for these mutations only (4). On the other hand the treatment combination
involving Lumafactor-ivacaftor had been effective in reducing the incidence of pulmonary
exacerbation Phe508del CFTR mutations. On the other hand for G551D mutations, triple
combination therapy treatment with two correctors and potentiator (tezacaftor-ivacaftor+VX-

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SYMDEKO™ FOR CYSTIC FIBROSIS
652) had reported best chloride transport. Therefore, it can be stated that it is crucial to use
different drugs to treat different mutations of the CFTR (4).
References:
1. Wise J. MPs call for fresh talks to end deadlock over cystic fibrosis drug. BMJ:
British Medical Journal (Online). 2018 Mar 21;360.
2. Gentzsch M, Cholon DM, Quinney NL, Boyles SE, Martino ME, Ribeiro CM. The
Cystic Fibrosis Airway Milieu Enhances Rescue of F508del in a Pre-Clinical Model.
European Respiratory Journal. 2018 Jan 1:1801133.
3. Sala MA, Jain M. Tezacaftor for the treatment of cystic fibrosis. Expert review of
respiratory medicine. 2018 Sep 2;12(9):725-32.
4. Van Goor F, Yu H, Burton B, Hoffman BJ. Effect of ivacaftor on CFTR forms with
missense mutations associated with defects in protein processing or function. Journal
of Cystic Fibrosis. 2014 Jan 1;13(1):29-36.